Childhood adversity correlates with stable changes in DNA methylation trajectories in children and converges with epigenetic signatures of prenatal stress.
Jade Martins, Darina Czamara, Susann Sauer, Monika Rex-Haffner, Katja Dittrich, Peggy Dörr, Karin de Punder, Judith Overfeld, Andrea Knop, Felix Dammering, Sonja Entringer, Sibylle M Winter, Claudia Buss, Christine Heim, Elisabeth B Binder
Childhood maltreatment (CM) is an established major risk factor for a number of negative health outcomes later in life. While epigenetic mechanisms, such as DNA methylation (DNAm), have been propos
ed as a means of embedding this environmental risk factor, little is known about its timing and trajectory, especially in very young children. It is also not clear whether additional environmental adversities, often experienced by these children, converge on similar DNAm changes. Here, we calculated a cumulative adversity score, which additionally to CM includes socioeconomic status (SES), other life events, parental psychopathology and epigenetic biomarkers of prenatal smoking and alcohol consumption. We investigated the effects of CM alone as well as the adversity score on longitudinal DNAm trajectories in the Berlin Longitudinal Child Study. This is a cohort of 173 children aged 3-5 years at baseline of whom 86 were exposed to CM. These children were followed-up for 2 years with extensive psychometric and biological assessments as well as saliva collection at 5 time points providing genome-wide DNAm levels. Overall, only a few DNAm patterns were stable over this timeframe, but less than 10 DNAm regions showed significant changes. At baseline, neither CM nor the adversity score associated with DNAm changes. However, in 6 differentially methylated regions (DMRs), CM and the adversity score significantly moderated DNAm trajectories over time. A number of these DMRs have previously been associated with adverse prenatal exposures. In our study, children exposed to CM also presented with epigenetic signatures indicative of increased prenatal exposure to tobacco and alcohol, as compared to non-CM exposed children. These epigenetic signatures of prenatal exposure strongly correlate with DNAm regions associated with CM and the adversity score. Finally, weighted correlation network analysis revealed a module of CpGs exclusively associated with CM. While our study identifies DNAm loci specifically associated with CM, especially within long non-coding RNAs, the majority of associations were found with the adversity score with convergent association with indicators of adverse prenatal exposures. This study highlights the importance of mapping not only of the epigenome but also the exposome and extending the observational timeframe to well before birth.
Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children's blood.
Carlos Ruiz-Arenas, Carles Hernandez-Ferrer, Marta Vives-Usano, Sergi Marí, Ines Quintela, Dan Mason, Solène Cadiou, Maribel Casas, Sandra Andrusaityte, Kristine Bjerve Gutzkow, Marina Vafeiadi, John Wright, Johanna Lepeule, Regina Grazuleviciene, Leda Chatzi, Ángel Carracedo, Xavier Estivill, Eulàlia Marti, Geòrgia Escaramís, Martine Vrijheid, Juan R González, Mariona Bustamante
The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epig
enome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children's blood, using data from 832 children of the Human Early Life Exposome (HELIX) project.
Transcriptome analysis of human adipocytes implicates the NOD-like receptor pathway in obesity-induced adipose inflammation.
Zheng Yin, Tuo Deng, Leif E Peterson, Richeng Yu, Jianxin Lin, Dale J Hamilton, Patrick R Reardon, Vadim Sherman, Glenn E Winnier, Ming Zhan, Christopher J Lyon, Stephen T C Wong, Willa A Hsueh
Adipose tissue inflammation increases with obesity, but adipocyte vs. immune cell contributions are unclear. In the present study, transcriptome analyses were performed on highly-purified subcutane
ous adipocytes from lean and obese women, and differentially expressed genes/pathways were determined in both adipocyte and stromal vascular fraction (SVF) samples. Adipocyte but not SVF expression of NOD-like receptor pathway genes, including NLRP3 and PYCARD, which regulate caspase-1-mediated IL-1β secretion, correlated with adiposity phenotypes and adipocyte class II major histocompatibility complex (MHCII) gene expression, but only MHCII remained after adjusting for age and body mass index. IFNγ stimulated adipocyte MHCII, NLRP3 and caspase-1 expression, while adipocyte MHCII-mediated CD4(+) T cell activation, an important factor in adipose inflammation, induced IFNγ-dependent adipocyte IL-1β secretion. These results uncover a dialogue regulated by interactions among T cell IFNγ and adipocyte MHCII and NLRP3 inflammasome activity that appears to initiate and escalate adipose tissue inflammation during obesity.
Changes in the transcriptome of abdominal subcutaneous adipose tissue in response to short-term overfeeding in lean and obese men.
Jennifer Shea, Curtis R French, Jessica Bishop, Glynn Martin, Barbara Roebothan, David Pace, Donald Fitzpatrick, Guang Sun
Obesity is caused by the excessive accumulation of adipose tissue as a result of a chronic energy surplus. Little is known regarding the molecular mechanisms involved in the response to an energy s
urplus in human adipose tissue at the genomic level.
Genetic regulation of the placental transcriptome underlies birth weight and risk of childhood obesity.
Shouneng Peng, Maya A Deyssenroth, Antonio F Di Narzo, Haoxiang Cheng, Zhongyang Zhang, Luca Lambertini, Arno Ruusalepp, Jason C Kovacic, Johan L M Bjorkegren, Carmen J Marsit, Jia Chen, Ke Hao
GWAS identified variants associated with birth weight (BW), childhood obesity (CO) and childhood BMI (CBMI), and placenta is a critical organ for fetal development and postnatal health. We examined
the role of placental transcriptome and eQTLs in mediating the genetic causes for BW, CO and CBMI, and applied integrative analysis (Colocalization and MetaXcan). GWAS loci associated with BW, CO, and CBMI were substantially enriched for placenta eQTLs (6.76, 4.83 and 2.26 folds, respectively). Importantly, compared to eQTLs of adult tissues, only placental eQTLs contribute significantly to both anthropometry outcomes at birth (BW) and childhood phenotypes (CO/CBMI). Eight, six and one transcripts colocalized with BW, CO and CBMI risk loci, respectively. Our study reveals that placental transcription in utero likely plays a key role in determining postnatal body size, and as such may hold new possibilities for therapeutic interventions to prevent childhood obesity.
Genome-wide DNA promoter methylation and transcriptome analysis in human adipose tissue unravels novel candidate genes for obesity.
Maria Keller, Lydia Hopp, Xuanshi Liu, Tobias Wohland, Kerstin Rohde, Raffaella Cancello, Matthias Klös, Karl Bacos, Matthias Kern, Fabian Eichelmann, Arne Dietrich, Michael R Schön, Daniel Gärtner, Tobias Lohmann, Miriam Dreßler, Michael Stumvoll, Peter Kovacs, Anna-Maria DiBlasio, Charlotte Ling, Hans Binder, Matthias Blüher, Yvonne Böttcher
DNA methylation plays an important role in obesity and related metabolic complications. We examined genome-wide DNA promoter methylation along with mRNA profiles in paired samples of human subcutan
eous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from non-obese
Prenatal maternal depressive symptoms and infant DNA methylation: a longitudinal epigenome-wide study.
Ellen Wikenius, Anne Margrethe Myhre, Christian Magnus Page, Vibeke Moe, Lars Smith, Einar Røshol Heiervang, Dag Erik Undlien, Marissa LeBlanc
Maternal prenatal stress and infant DNA methylation: A systematic review.
David W Sosnowski, Carolyn Booth, Timothy P York, Ananda B Amstadter, Wendy Kliewer
Maternal prenatal stress has been linked to a variety of infant postnatal outcomes, partially through alterations in fetal HPA axis functioning; yet the underlying pathobiology remains elusive. Cur
rent literature posits DNA methylation as a candidate mechanism through which maternal prenatal stress can influence fetal HPA axis functioning. The goal of this systematic review was to summarize the literature examining the associations among maternal prenatal stress, DNA methylation of commonly studied HPA axis candidate genes, and infant HPA axis functioning. Results from the review provided evidence for a link between various maternal prenatal stressors, NR3C1 methylation, and infant stress reactivity, but findings among other genes were limited, with mixed results. An original study quality review tool revealed that a majority of studies in the review are adequate, and emphasizes the need for future research to consider study quality when interpreting research findings.
DNA-Methylation and Body Composition in Preschool Children: Epigenome-Wide-Analysis in the European Childhood Obesity Project (CHOP)-Study.
Peter Rzehak, Marcela Covic, Richard Saffery, Eva Reischl, Simone Wahl, Veit Grote, Martina Weber, Annick Xhonneux, Jean-Paul Langhendries, Natalia Ferre, Ricardo Closa-Monasterolo, Joaquin Escribano, Elvira Verduci, Enrica Riva, Piotr Socha, Dariusz Gruszfeld, Berthold Koletzko
Adiposity and obesity result from the interaction of genetic variation and environmental factors from very early in life, possibly mediated by epigenetic processes. Few Epigenome-Wide-Association-S
tudies have identified DNA-methylation (DNAm) signatures associated with BMI and body composition in children. Body composition by Bio-Impedance-Analysis and genome-wide DNAm in whole blood were assessed in 374 pre-school children from four European countries. Associations were tested by linear regression adjusted for sex, age, centre, education, 6 WBC-proportions according to Houseman and 30 principal components derived from control probes. Specific DNAm variants were identified to be associated with BMI (212), fat-mass (230), fat-free-mass (120), fat-mass-index (24) and fat-free-mass-index (15). Probes in genes SNED1(IRE-BP1), KLHL6, WDR51A(POC1A), CYTH4-ELFN2, CFLAR, PRDM14, SOS1, ZNF643(ZFP69B), ST6GAL1, C3orf70, CILP2, MLLT4 and ncRNA LOC101929268 remained significantly associated after Bonferroni-correction of P-values. We provide novel evidence linking DNAm with (i) altered lipid and glucose metabolism, (ii) diabetes and (iii) body size and composition in children. Both common and specific epigenetic signatures among measures were also revealed. The causal direction with phenotypic measures and stability of DNAm variants throughout the life course remains unclear and longitudinal analysis in other populations is required. These findings give support for potential epigenetic programming of body composition and obesity.
Translating GWAS findings into therapies for depression and anxiety disorders: gene-set analyses reveal enrichment of psychiatric drug classes and implications for drug repositioning.
Hon-Cheong So, Carlos Kwan-Long Chau, Alexandria Lau, Sze-Yung Wong, Kai Zhao
Depression and anxiety disorders (AD) are the first and sixth leading causes of disability worldwide. Despite their high prevalence and significant disability resulted, there are limited advances i
n new drug development. Recently, genome-wide association studies (GWAS) have greatly advanced our understanding of the genetic basis underlying psychiatric disorders.
Uncomplicated human obesity is associated with a specific cardiac transcriptome: involvement of the Wnt pathway.
Pierre Philip-Couderc, Atul Pathak, Fatima Smih, Camille Dambrin, Romain Harmancey, Sophie Buys, Michel Galinier, Pierre Massabuau, Jerome Roncalli, Jean-Michel Senard, Philippe Rouet
A dramatic increase in obesity prevalence and cardiovascular morbidity is expected for the coming years. However, with relevance to the heart, little is known about the specific contribution of obe
sity on associated morbidity. Consequently, global analysis of gene regulations in human heart was undertaken to monitor molecular regulations related to obesity or to obesity-related hypertension. Transcriptome analysis using cDNA arrays was performed in right appendage biopsies from obese patients (n=5), from patients with arterial hypertension with (n=5) or without obesity (n=5), and from 5 leans. All biopsies came from patients that had cardiac surgery and coronary bypass. Statistical analysis of the data revealed 2686 differentially expressed genes out of 11,500 when compared with lean tissues. Differential expression was verified by real-time PCR in 84% of 50 randomly chosen genes. Among genes encountered, 397 were specifically regulated in obese, 1,299 in non-obese hypertensive, and 355 in obese hypertensive patients, respectively, whereas an additional set of 153 genes was differentially expressed in all these situations. Ontology analysis, hierarchical clustering, and molecular pathway analysis indicated that the heart molecular picture of obesity differs clearly from that observed for obesity-related hypertension or arterial hypertension. Clearly, the Wnt pathway known to be involved in cardiac hypertrophy mechanisms, showed opposite regulation in obese heart compared with hypertensive heart and potentially prevented the development of cardiac remodeling in obese patients. All over, this work shows that uncomplicated obesity has a strong impact on cardiac gene expression, which could be considered as precursor signs for future cardiac disease and also demonstrates that obesity-related hypertension generates a heart-molecular-distinct phenotype that cannot be predicted by a simple sum of the impact of obesity and arterial hypertension on gene expression.
Diurnal variation of the human adipose transcriptome and the link to metabolic disease.
Andrey Loboda, Walter K Kraft, Bernard Fine, Jeffrey Joseph, Michael Nebozhyn, Chunsheng Zhang, Yudong He, Xia Yang, Christopher Wright, Mark Morris, Ira Chalikonda, Mark Ferguson, Valur Emilsson, Amy Leonardson, John Lamb, Hongyue Dai, Eric Schadt, Howard E Greenberg, Pek Yee Lum
Circadian (diurnal) rhythm is an integral part of the physiology of the body; specifically, sleep, feeding behavior and metabolism are tightly linked to the light-dark cycle dictated by earth's rot
Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring.
Fabiola C R Zucchi, Youli Yao, Isaac D Ward, Yaroslav Ilnytskyy, David M Olson, Karen Benzies, Igor Kovalchuk, Olga Kovalchuk, Gerlinde A S Metz
The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health
and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease.
Prenatal maternal stress and wheeze in children: novel insights into epigenetic regulation.
Saskia Trump, Matthias Bieg, Zuguang Gu, Loreen Thürmann, Tobias Bauer, Mario Bauer, Naveed Ishaque, Stefan Röder, Lei Gu, Gunda Herberth, Christian Lawerenz, Michael Borte, Matthias Schlesner, Christoph Plass, Nicolle Diessl, Markus Eszlinger, Oliver Mücke, Horst-Dietrich Elvers, Dirk K Wissenbach, Martin von Bergen, Carl Herrmann, Dieter Weichenhan, Rosalind J Wright, Irina Lehmann, Roland Eils
Psychological stress during pregnancy increases the risk of childhood wheeze and asthma. However, the transmitting mechanisms remain largely unknown. Since epigenetic alterations have emerged as a
link between perturbations in the prenatal environment and an increased disease risk we used whole genome bisulfite sequencing (WGBS) to analyze changes in DNA methylation in mothers and their children related to prenatal psychosocial stress and assessed its role in the development of wheeze in the child. We evaluated genomic regions altered in their methylation level due to maternal stress based of WGBS data of 10 mother-child-pairs. These data were complemented by longitudinal targeted methylation and transcriptional analyses in children from our prospective mother-child cohort LINA for whom maternal stress and wheezing information was available (n = 443). High maternal stress was associated with an increased risk for persistent wheezing in the child until the age of 5. Both mothers and children showed genome-wide alterations in DNA-methylation specifically in enhancer elements. Deregulated neuroendocrine and neurotransmitter receptor interactions were observed in stressed mothers and their children. In children but not in mothers, calcium- and Wnt-signaling required for lung maturation in the prenatal period were epigenetically deregulated and could be linked with wheezing later in children's life.
Grandmaternal stress during pregnancy and DNA methylation of the third generation: an epigenome-wide association study.
F Serpeloni, K Radtke, S G de Assis, F Henning, D Nätt, T Elbert
Stress during pregnancy may impact subsequent generations, which is demonstrated by an increased susceptibility to childhood and adulthood health problems in the children and grandchildren. Althoug
h the importance of the prenatal environment is well reported with regards to future physical and emotional outcomes, little is known about the molecular mechanisms that mediate the long-term consequences of early stress across generations. Recent studies have identified DNA methylation as a possible mediator of the impact of prenatal stress in the offspring. Whether psychosocial stress during pregnancy also affects DNA methylation of the grandchildren is still not known. In the present study we examined the multigenerational hypothesis, that is, grandmaternal exposure to psychosocial stress during pregnancy affecting DNA methylation of the grandchildren. We determined the genome-wide DNA methylation profile in 121 children (65 females and 56 males) and tested for associations with exposure to grandmaternal interpersonal violence during pregnancy. We observed methylation variations of five CpG sites significantly (FDR<0.05) associated with the grandmother's report of exposure to violence while pregnant with the mothers of the children. The results revealed differential methylation of genes previously shown to be involved in circulatory system processes (FDR<0.05). This study provides support for DNA methylation as a biological mechanism involved in the transmission of stress across generations and motivates further investigations to examine prenatal-dependent DNA methylation as a potential biomarker for health problems.
Does maternal mental well-being in pregnancy impact the early human epigenome?
Joanne Ryan, Toby Mansell, Peter Fransquet, Richard Saffery
There is considerable interest in the potential nongenetic transmission of a suite of mental health conditions across generations, with epigenetics emerging as a candidate mediator of such effects.
This review summarizes findings from 22 studies measuring candidate gene DNA methylation and seven epigenome-wide association studies of offspring epigenetic profile in women with adverse mental wellbeing measures (stress, depression or anxiety) in pregnancy. Despite some compelling evidence to suggest an association, there is a lack of reproducible findings, potentially linked to a number of limitations to this research and the field more broadly. Large cohorts with well characterized exposures across pregnancy are now needed. There is exciting potential that epigenetics may help explain some of the link between maternal wellbeing and child health outcomes, thereby informing novel interventions, but future studies must address current limitations to advance translational knowledge in this area.
Prenatal Stress, Fearfulness, and the Epigenome: Exploratory Analysis of Sex Differences in DNA Methylation of the Glucocorticoid Receptor Gene.
Brendan D Ostlund, Elisabeth Conradt, Sheila E Crowell, Audrey R Tyrka, Carmen J Marsit, Barry M Lester
Exposure to stress in utero is a risk factor for the development of problem behavior in the offspring, though precise pathways are unknown. We examined whether DNA methylation of the glucocorticoid
receptor gene, NR3C1, was associated with experiences of stress by an expectant mother and fearfulness in her infant. Mothers reported on prenatal stress and infant temperament when infants were 5 months old (n = 68). Buccal cells for methylation analysis were collected from each infant. Prenatal stress was not related to infant fearfulness or NR3C1 methylation in the sample as a whole. Exploratory sex-specific analysis revealed a trend-level association between prenatal stress and increased methylation of NR3C1 exon 1F for female, but not male, infants. In addition, increased methylation was significantly associated with greater fearfulness for females. Results suggest an experience-dependent pathway to fearfulness for female infants via epigenetic modification of the glucocorticoid receptor gene. Future studies should examine prenatal stress in a comprehensive fashion while considering sex differences in epigenetic processes underlying infant temperament.
An epigenome-wide DNA methylation study of PTSD and depression in World Trade Center responders.
P-F Kuan, M A Waszczuk, R Kotov, C J Marsit, G Guffanti, A Gonzalez, X Yang, K Koenen, E Bromet, B J Luft
Previous epigenome-wide association studies (EWAS) of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) have been inconsistent. This may be due to small sample sizes, and mea
surement and tissue differences. The current two EWA analyses of 473 World Trade Center responders are the largest to date for both PTSD and MDD. These analyses investigated DNA methylation patterns and biological pathways influenced by differentially methylated genes associated with each disorder. Methylation was profiled on blood samples using Illumina 450 K Beadchip. Two EWA analyses compared current versus never PTSD, and current versus never MDD, adjusting for cell types and demographic confounders. Pathway and gene set enrichment analyses were performed to understand the complex biological systems of PTSD and MDD. No significant epigenome-wide associations were found for PTSD or MDD at an FDR P<0.05. The majority of genes with differential methylation at a suggestive threshold did not overlap between the two disorders. Pathways significant in PTSD included a regulator of synaptic plasticity, oxytocin signaling, cholinergic synapse and inflammatory disease pathways, while only phosphatidylinositol signaling and cell cycle pathways emerged in MDD. The failure of the current EWA analyses to detect significant epigenome-wide associations is in contrast with disparate findings from previous, smaller EWA and candidate gene studies of PTSD and MDD. Enriched gene sets involved in several biological pathways, including stress response, inflammation and physical health, were identified in PTSD, supporting the view that multiple genes play a role in this complex disorder.
An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: A model approach for replication.
Jolien Rijlaarsdam, Irene Pappa, Esther Walton, Marian J Bakermans-Kranenburg, Viara R Mileva-Seitz, Ralph C A Rippe, Sabine J Roza, Vincent W V Jaddoe, Frank C Verhulst, Janine F Felix, Charlotte A M Cecil, Caroline L Relton, Tom R Gaunt, Wendy McArdle, Jonathan Mill, Edward D Barker, Henning Tiemeier, Marinus H van IJzendoorn
Prenatal maternal stress exposure has been associated with neonatal differential DNA methylation. However, the available evidence in humans is largely based on candidate gene methylation studies, w
here only a few CpG sites were evaluated. The aim of this study was to examine the association between prenatal exposure to maternal stress and offspring genome-wide cord blood methylation using different methods. First, we conducted a meta-analysis and follow-up pathway analyses. Second, we used novel region discovery methods [i.e., differentially methylated regions (DMRs) analyses]. To this end, we used data from two independent population-based studies, the Generation R Study (n = 912) and the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 828), to (i) measure genome-wide DNA methylation in cord blood and (ii) extract a prenatal maternal stress composite. The meta-analysis (ntotal = 1,740) revealed no epigenome-wide (meta P <1.00e-07) associations of prenatal maternal stress exposure with neonatal differential DNA methylation. Follow-up analyses of the top hits derived from our epigenome-wide meta-analysis (meta P <1.00e-04) indicated an over-representation of the methyltransferase activity pathway. We identified no Bonferroni-corrected (P <1.00e-06) DMRs associated with prenatal maternal stress exposure. Combining data from two independent population-based samples in an epigenome-wide meta-analysis, the current study indicates that there are no large effects of prenatal maternal stress exposure on neonatal DNA methylation. Such replication efforts are essential in the search for robust associations, whether derived from candidate gene methylation or epigenome-wide studies.
Positive correlation of cg16672562 methylation with obesity-related traits in childhood obesity, and its independence with underlying
Suman Lee, Hyo Jin Kim, Sohee Han, Jae-Pil Jeon, Sang-Ick Park, Ho-Yeong Yu, Mi Yeong Hwang, Juyoung Lee
Differential methylations of the
The Epigenomic Analysis of Human Obesity.
Christopher G Bell
Analysis of the epigenome-the chemical modifications and packaging of the genome that can influence or indicate its activity-enables molecular insight into cell type-specific machinery. It can, the
refore, reveal the pathophysiological mechanisms at work in disease. Detected changes can also represent physiological responses to adverse environmental exposures, thus enabling the epigenetic mark of DNA methylation to act as an epidemiological biomarker, even in surrogate tissue. This makes epigenomic analysis an attractive prospect to further understand the pathobiology and epidemiological aspects of obesity. Furthermore, integrating epigenomic data with known obesity-associated common genetic variation can aid in deciphering their molecular mechanisms.
Shared Genetic Loci Between Body Mass Index and Major Psychiatric Disorders: A Genome-wide Association Study.
Shahram Bahrami, Nils Eiel Steen, Alexey Shadrin, Kevin O'Connell, Oleksandr Frei, Francesco Bettella, Katrine V Wirgenes, Florian Krull, Chun C Fan, Anders M Dale, Olav B Smeland, Srdjan Djurovic, Ole A Andreassen
People with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome
-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown.
Osteoporosis- and obesity-risk interrelationships: an epigenetic analysis of GWAS-derived SNPs at the developmental gene
Xiao Zhang, Kenneth C Ehrlich, Fangtang Yu, Xiaojun Hu, Xiang-He Meng, Hong-Wen Deng, Hui Shen, Melanie Ehrlich
A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants as
sociated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the
Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned.
N R Wray, M L Pergadia, D H R Blackwood, B W J H Penninx, S D Gordon, D R Nyholt, S Ripke, D J MacIntyre, K A McGhee, A W Maclean, J H Smit, J J Hottenga, G Willemsen, C M Middeldorp, E J C de Geus, C M Lewis, P McGuffin, I B Hickie, E J C G van den Oord, J Z Liu, S Macgregor, B P McEvoy, E M Byrne, S E Medland, D J Statham, A K Henders, A C Heath, G W Montgomery, N G Martin, D I Boomsma, P A F Madden, P F Sullivan
Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls
and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.
New genetic loci link adipose and insulin biology to body fat distribution.
Dmitry Shungin, Thomas W Winkler, Damien C Croteau-Chonka, Teresa Ferreira, Adam E Locke, Reedik Mägi, Rona J Strawbridge, Tune H Pers, Krista Fischer, Anne E Justice, Tsegaselassie Workalemahu, Joseph M W Wu, Martin L Buchkovich, Nancy L Heard-Costa, Tamara S Roman, Alexander W Drong, Ci Song, Stefan Gustafsson, Felix R Day, Tonu Esko, Tove Fall, Zoltán Kutalik, Jian'an Luan, Joshua C Randall, André Scherag, Sailaja Vedantam, Andrew R Wood, Jin Chen, Rudolf Fehrmann, Juha Karjalainen, Bratati Kahali, Ching-Ti Liu, Ellen M Schmidt, Devin Absher, Najaf Amin, Denise Anderson, Marian Beekman, Jennifer L Bragg-Gresham, Steven Buyske, Ayse Demirkan, Georg B Ehret, Mary F Feitosa, Anuj Goel, Anne U Jackson, Toby Johnson, Marcus E Kleber, Kati Kristiansson, Massimo Mangino, Irene Mateo Leach, Carolina Medina-Gomez, Cameron D Palmer, Dorota Pasko, Sonali Pechlivanis, Marjolein J Peters, Inga Prokopenko, Alena Stančáková, Yun Ju Sung, Toshiko Tanaka, Alexander Teumer, Jana V Van Vliet-Ostaptchouk, Loïc Yengo, Weihua Zhang, Eva Albrecht, Johan Ärnlöv, Gillian M Arscott, Stefania Bandinelli, Amy Barrett, Claire Bellis, Amanda J Bennett, Christian Berne, Matthias Blüher, Stefan Böhringer, Fabrice Bonnet, Yvonne Böttcher, Marcel Bruinenberg, Delia B Carba, Ida H Caspersen, Robert Clarke, E Warwick Daw, Joris Deelen, Ewa Deelman, Graciela Delgado, Alex Sf Doney, Niina Eklund, Michael R Erdos, Karol Estrada, Elodie Eury, Nele Friedrich, Melissa E Garcia, Vilmantas Giedraitis, Bruna Gigante, Alan S Go, Alain Golay, Harald Grallert, Tanja B Grammer, Jürgen Gräßler, Jagvir Grewal, Christopher J Groves, Toomas Haller, Goran Hallmans, Catharina A Hartman, Maija Hassinen, Caroline Hayward, Kauko Heikkilä, Karl-Heinz Herzig, Quinta Helmer, Hans L Hillege, Oddgeir Holmen, Steven C Hunt, Aaron Isaacs, Till Ittermann, Alan L James, Ingegerd Johansson, Thorhildur Juliusdottir, Ioanna-Panagiota Kalafati, Leena Kinnunen, Wolfgang Koenig, Ishminder K Kooner, Wolfgang Kratzer, Claudia Lamina, Karin Leander, Nanette R Lee, Peter Lichtner, Lars Lind, Jaana Lindström, Stéphane Lobbens, Mattias Lorentzon, François Mach, Patrik Ke Magnusson, Anubha Mahajan, Wendy L McArdle, Cristina Menni, Sigrun Merger, Evelin Mihailov, Lili Milani, Rebecca Mills, Alireza Moayyeri, Keri L Monda, Simon P Mooijaart, Thomas W Mühleisen, Antonella Mulas, Gabriele Müller, Martina Müller-Nurasyid, Ramaiah Nagaraja, Michael A Nalls, Narisu Narisu, Nicola Glorioso, Ilja M Nolte, Matthias Olden, Nigel W Rayner, Frida Renstrom, Janina S Ried, Neil R Robertson, Lynda M Rose, Serena Sanna, Hubert Scharnagl, Salome Scholtens, Bengt Sennblad, Thomas Seufferlein, Colleen M Sitlani, Albert Vernon Smith, Kathleen Stirrups, Heather M Stringham, Johan Sundström, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Bamidele O Tayo, Barbara Thorand, Gudmar Thorleifsson, Andreas Tomaschitz, Chiara Troffa, Floor Va van Oort, Niek Verweij, Judith M Vonk, Lindsay L Waite, Roman Wennauer, Tom Wilsgaard, Mary K Wojczynski, Andrew Wong, Qunyuan Zhang, Jing Hua Zhao, Eoin P Brennan, Murim Choi, Per Eriksson, Lasse Folkersen, Anders Franco-Cereceda, Ali G Gharavi, Åsa K Hedman, Marie-France Hivert, Jinyan Huang, Stavroula Kanoni, Fredrik Karpe, Sarah Keildson, Krzysztof Kiryluk, Liming Liang, Richard P Lifton, Baoshan Ma, Amy J McKnight, Ruth McPherson, Andres Metspalu, Josine L Min, Miriam F Moffatt, Grant W Montgomery, Joanne M Murabito, George Nicholson, Dale R Nyholt, Christian Olsson, John Rb Perry, Eva Reinmaa, Rany M Salem, Niina Sandholm, Eric E Schadt, Robert A Scott, Lisette Stolk, Edgar E Vallejo, Harm-Jan Westra, Krina T Zondervan, None None, None None, None None, None None, None None, None None, None None, None None, None None, None None, None None, None None, None None, Philippe Amouyel, Dominique Arveiler, Stephan Jl Bakker, John Beilby, Richard N Bergman, John Blangero, Morris J Brown, Michel Burnier, Harry Campbell, Aravinda Chakravarti, Peter S Chines, Simone Claudi-Boehm, Francis S Collins, Dana C Crawford, John Danesh, Ulf de Faire, Eco Jc de Geus, Marcus Dörr, Raimund Erbel, Johan G Eriksson, Martin Farrall, Ele Ferrannini, Jean Ferrières, Nita G Forouhi, Terrence Forrester, Oscar H Franco, Ron T Gansevoort, Christian Gieger, Vilmundur Gudnason, Christopher A Haiman, Tamara B Harris, Andrew T Hattersley, Markku Heliövaara, Andrew A Hicks, Aroon D Hingorani, Wolfgang Hoffmann, Albert Hofman, Georg Homuth, Steve E Humphries, Elina Hyppönen, Thomas Illig, Marjo-Riitta Jarvelin, Berit Johansen, Pekka Jousilahti, Antti M Jula, Jaakko Kaprio, Frank Kee, Sirkka M Keinanen-Kiukaanniemi, Jaspal S Kooner, Charles Kooperberg, Peter Kovacs, Aldi T Kraja, Meena Kumari, Kari Kuulasmaa, Johanna Kuusisto, Timo A Lakka, Claudia Langenberg, Loic Le Marchand, Terho Lehtimäki, Valeriya Lyssenko, Satu Männistö, André Marette, Tara C Matise, Colin A McKenzie, Barbara McKnight, Arthur W Musk, Stefan Möhlenkamp, Andrew D Morris, Mari Nelis, Claes Ohlsson, Albertine J Oldehinkel, Ken K Ong, Lyle J Palmer, Brenda W Penninx, Annette Peters, Peter P Pramstaller, Olli T Raitakari, Tuomo Rankinen, D C Rao, Treva K Rice, Paul M Ridker, Marylyn D Ritchie, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Jouko Saramies, Mark A Sarzynski, Peter Eh Schwarz, Alan R Shuldiner, Jan A Staessen, Valgerdur Steinthorsdottir, Ronald P Stolk, Konstantin Strauch, Anke Tönjes, Angelo Tremblay, Elena Tremoli, Marie-Claude Vohl, Uwe Völker, Peter Vollenweider, James F Wilson, Jacqueline C Witteman, Linda S Adair, Murielle Bochud, Bernhard O Boehm, Stefan R Bornstein, Claude Bouchard, Stéphane Cauchi, Mark J Caulfield, John C Chambers, Daniel I Chasman, Richard S Cooper, George Dedoussis, Luigi Ferrucci, Philippe Froguel, Hans-Jörgen Grabe, Anders Hamsten, Jennie Hui, Kristian Hveem, Karl-Heinz Jöckel, Mika Kivimaki, Diana Kuh, Markku Laakso, Yongmei Liu, Winfried März, Patricia B Munroe, Inger Njølstad, Ben A Oostra, Colin Na Palmer, Nancy L Pedersen, Markus Perola, Louis Pérusse, Ulrike Peters, Chris Power, Thomas Quertermous, Rainer Rauramaa, Fernando Rivadeneira, Timo E Saaristo, Danish Saleheen, Juha Sinisalo, P Eline Slagboom, Harold Snieder, Tim D Spector, Kari Stefansson, Michael Stumvoll, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, Pim van der Harst, Giovanni Veronesi, Mark Walker, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, Goncalo R Abecasis, Themistocles L Assimes, Sonja I Berndt, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Lude Franke, Timothy M Frayling, Leif C Groop, David J Hunter, Robert C Kaplan, Jeffrey R O'Connell, Lu Qi, David Schlessinger, David P Strachan, Unnur Thorsteinsdottir, Cornelia M van Duijn, Cristen J Willer, Peter M Visscher, Jian Yang, Joel N Hirschhorn, M Carola Zillikens, Mark I McCarthy, Elizabeth K Speliotes, Kari E North, Caroline S Fox, Inês Barroso, Paul W Franks, Erik Ingelsson, Iris M Heid, Ruth Jf Loos, L Adrienne Cupples, Andrew P Morris, Cecilia M Lindgren, Karen L Mohlke
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of bo
dy fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.
Aysu Okbay, Bart M L Baselmans, Jan-Emmanuel De Neve, Patrick Turley, Michel G Nivard, Mark Alan Fontana, S Fleur W Meddens, Richard Karlsson Linnér, Cornelius A Rietveld, Jaime Derringer, Jacob Gratten, James J Lee, Jimmy Z Liu, Ronald de Vlaming, Tarunveer S Ahluwalia, Jadwiga Buchwald, Alana Cavadino, Alexis C Frazier-Wood, Nicholas A Furlotte, Victoria Garfield, Marie Henrike Geisel, Juan R Gonzalez, Saskia Haitjema, Robert Karlsson, Sander W van der Laan, Karl-Heinz Ladwig, Jari Lahti, Sven J van der Lee, Penelope A Lind, Tian Liu, Lindsay Matteson, Evelin Mihailov, Michael B Miller, Camelia C Minica, Ilja M Nolte, Dennis Mook-Kanamori, Peter J van der Most, Christopher Oldmeadow, Yong Qian, Olli Raitakari, Rajesh Rawal, Anu Realo, Rico Rueedi, Börge Schmidt, Albert V Smith, Evie Stergiakouli, Toshiko Tanaka, Kent Taylor, Gudmar Thorleifsson, Juho Wedenoja, Juergen Wellmann, Harm-Jan Westra, Sara M Willems, Wei Zhao, None None, Najaf Amin, Andrew Bakshi, Sven Bergmann, Gyda Bjornsdottir, Patricia A Boyle, Samantha Cherney, Simon R Cox, Gail Davies, Oliver S P Davis, Jun Ding, Nese Direk, Peter Eibich, Rebecca T Emeny, Ghazaleh Fatemifar, Jessica D Faul, Luigi Ferrucci, Andreas J Forstner, Christian Gieger, Richa Gupta, Tamara B Harris, Juliette M Harris, Elizabeth G Holliday, Jouke-Jan Hottenga, Philip L De Jager, Marika A Kaakinen, Eero Kajantie, Ville Karhunen, Ivana Kolcic, Meena Kumari, Lenore J Launer, Lude Franke, Ruifang Li-Gao, David C Liewald, Marisa Koini, Anu Loukola, Pedro Marques-Vidal, Grant W Montgomery, Miriam A Mosing, Lavinia Paternoster, Alison Pattie, Katja E Petrovic, Laura Pulkki-Råback, Lydia Quaye, Katri Räikkönen, Igor Rudan, Rodney J Scott, Jennifer A Smith, Angelina R Sutin, Maciej Trzaskowski, Anna E Vinkhuyzen, Lei Yu, Delilah Zabaneh, John R Attia, David A Bennett, Klaus Berger, Lars Bertram, Dorret I Boomsma, Harold Snieder, Shun-Chiao Chang, Francesco Cucca, Ian J Deary, Cornelia M van Duijn, Johan G Eriksson, Ute Bültmann, Eco J C de Geus, Patrick J F Groenen, Vilmundur Gudnason, Torben Hansen, Catharine A Hartman, Claire M A Haworth, Caroline Hayward, Andrew C Heath, David A Hinds, Elina Hyppönen, William G Iacono, Marjo-Riitta Järvelin, Karl-Heinz Jöckel, Jaakko Kaprio, Sharon L R Kardia, Liisa Keltikangas-Järvinen, Peter Kraft, Laura D Kubzansky, Terho Lehtimäki, Patrik K E Magnusson, Nicholas G Martin, Matt McGue, Andres Metspalu, Melinda Mills, Renée de Mutsert, Albertine J Oldehinkel, Gerard Pasterkamp, Nancy L Pedersen, Robert Plomin, Ozren Polasek, Christine Power, Stephen S Rich, Frits R Rosendaal, Hester M den Ruijter, David Schlessinger, Helena Schmidt, Rauli Svento, Reinhold Schmidt, Behrooz Z Alizadeh, Thorkild I A Sørensen, Tim D Spector, John M Starr, Kari Stefansson, Andrew Steptoe, Antonio Terracciano, Unnur Thorsteinsdottir, A Roy Thurik, Nicholas J Timpson, Henning Tiemeier, André G Uitterlinden, Peter Vollenweider, Gert G Wagner, David R Weir, Jian Yang, Dalton C Conley, George Davey Smith, Albert Hofman, Magnus Johannesson, David I Laibson, Sarah E Medland, Michelle N Meyer, Joseph K Pickrell, Tõnu Esko, Robert F Krueger, Jonathan P Beauchamp, Philipp D Koellinger, Daniel J Benjamin, Meike Bartels, David Cesarini
Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetica
lly correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
Depression Heterogeneity and Its Biological Underpinnings: Toward Immunometabolic Depression.
Yuri Milaneschi, Femke Lamers, Michael Berk, Brenda W J H Penninx
Epidemiological evidence indicates the presence of dysregulated homeostatic biological pathways in depressed patients, such as increased inflammation and disrupted energy-regulating neuroendocrine
signaling (e.g., leptin, insulin). Alterations in these biological pathways may explain the considerable comorbidity between depression and cardiometabolic conditions (e.g., obesity, metabolic syndrome, diabetes) and represent a promising target for intervention. This review describes how immunometabolic dysregulations vary as a function of depression heterogeneity by illustrating that such biological dysregulations map more consistently to atypical behavioral symptoms reflecting altered energy intake/expenditure balance (hyperphagia, weight gain, hypersomnia, fatigue, and leaden paralysis) and may moderate the antidepressant effects of standard or novel (e.g., anti-inflammatory) therapeutic approaches. These lines of evidence are integrated in a conceptual model of immunometabolic depression emerging from the clustering of immunometabolic biological dysregulations and specific behavioral symptoms. The review finally elicits questions to be answered by future research and describes how the immunometabolic depression dimension could be used to dissect the heterogeneity of depression and potentially to match subgroups of patients to specific treatments with higher likelihood of clinical success.
Role of BMI-associated loci identified in GWAS meta-analyses in the context of common childhood obesity in European Americans.
Jianhua Zhao, Jonathan P Bradfield, Haitao Zhang, Patrick M Sleiman, Cecilia E Kim, Joseph T Glessner, Sandra Deliard, Kelly A Thomas, Edward C Frackelton, Mingyao Li, Rosetta M Chiavacci, Robert I Berkowitz, Hakon Hakonarson, Struan F A Grant
Obesity is a serious health concern for children and adolescents, particularly in Western societies, where its incidence is now considered to have reached epidemic proportions. A number of genetic
determinants of adult BMI have already been established through genome wide association studies (GWAS), most recently from the GIANT meta-analysis of such datasets combined. In this current study of European Americans, we examined the 32 loci detected in that GIANT study in the context of common childhood obesity within a cohort of 1,097 cases (defined as BMI ≥95th percentile), together with 2,760 lean controls (defined as BMI <50th percentile), aged between 2 and 18 years old. Nine of these single-nucleotide polymorphims (SNPs) yielded at least nominal evidence for association with common childhood obesity, namely at the FTO, TMEM18, NRXN3, MC4R, SEC16B, GNPDA2, TNNI3K, QPCTL, and BDNF loci. However, overall 28 of the 32 loci showed directionally consistent effects to that of the adult BMI meta-analysis. We conclude that among the 32 loci that have been reported to associate with adult BMI in the largest meta-analysis of BMI to date, at least nine also contribute to the determination of common obesity in childhood in European Americans, as demonstrated by their associations in our pediatric cohort.
Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
Naomi R Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M Byrne, Abdel Abdellaoui, Mark J Adams, Esben Agerbo, Tracy M Air, Till M F Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan F T Beekman, Tim B Bigdeli, Elisabeth B Binder, Douglas R H Blackwood, Julien Bryois, Henriette N Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, Jonathan I R Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E Crawford, Cheynna A Crowley, Hassan S Dashti, Gail Davies, Ian J Deary, Franziska Degenhardt, Eske M Derks, Nese Direk, Conor V Dolan, Erin C Dunn, Thalia C Eley, Nicholas Eriksson, Valentina Escott-Price, Farnush Hassan Farhadi Kiadeh, Hilary K Finucane, Andreas J Forstner, Josef Frank, Héléna A Gaspar, Michael Gill, Paola Giusti-Rodríguez, Fernando S Goes, Scott D Gordon, Jakob Grove, Lynsey S Hall, Eilis Hannon, Christine Søholm Hansen, Thomas F Hansen, Stefan Herms, Ian B Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M Hougaard, Ming Hu, Craig L Hyde, Marcus Ising, Rick Jansen, Fulai Jin, Eric Jorgenson, James A Knowles, Isaac S Kohane, Julia Kraft, Warren W Kretzschmar, Jesper Krogh, Zoltán Kutalik, Jacqueline M Lane, Yihan Li, Yun Li, Penelope A Lind, Xiaoxiao Liu, Leina Lu, Donald J MacIntyre, Dean F MacKinnon, Robert M Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E Medland, Divya Mehta, Christel M Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Jonathan Mill, Francis M Mondimore, Grant W Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G Nivard, Dale R Nyholt, Paul F O'Reilly, Hogni Oskarsson, Michael J Owen, Jodie N Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E Peterson, Erik Pettersson, Wouter J Peyrot, Giorgio Pistis, Danielle Posthuma, Shaun M Purcell, Jorge A Quiroz, Per Qvist, John P Rice, Brien P Riley, Margarita Rivera, Saira Saeed Mirza, Richa Saxena, Robert Schoevers, Eva C Schulte, Ling Shen, Jianxin Shi, Stanley I Shyn, Engilbert Sigurdsson, Grant B C Sinnamon, Johannes H Smit, Daniel J Smith, Hreinn Stefansson, Stacy Steinberg, Craig A Stockmeier, Fabian Streit, Jana Strohmaier, Katherine E Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A Thomson, Thorgeir E Thorgeirsson, Chao Tian, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M van Hemert, Alexander Viktorin, Peter M Visscher, Yunpeng Wang, Bradley T Webb, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H Witt, Yang Wu, Hualin S Xi, Jian Yang, Futao Zhang, None None, None None, Volker Arolt, Bernhard T Baune, Klaus Berger, Dorret I Boomsma, Sven Cichon, Udo Dannlowski, E C J de Geus, J Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tõnu Esko, Hans J Grabe, Steven P Hamilton, Caroline Hayward, Andrew C Heath, David A Hinds, Kenneth S Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S Li, Susanne Lucae, Pamela F A Madden, Patrik K Magnusson, Nicholas G Martin, Andrew M McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M Nöthen, Michael C O'Donovan, Sara A Paciga, Nancy L Pedersen, Brenda W J H Penninx, Roy H Perlis, David J Porteous, James B Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas G Schulze, Jordan W Smoller, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M Weissman, Thomas Werge, Ashley R Winslow, Cathryn M Lewis, Douglas F Levinson, Gerome Breen, Anders D Børglum, Patrick F Sullivan, None None
Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis bas
ed in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
A genome-wide association study on obesity and obesity-related traits.
Kai Wang, Wei-Dong Li, Clarence K Zhang, Zuoheng Wang, Joseph T Glessner, Struan F A Grant, Hongyu Zhao, Hakon Hakonarson, R Arlen Price
Large-scale genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI), but few studies focused on obesity as a binary trait. Here we report the results
of a GWAS and candidate SNP genotyping study of obesity, including extremely obese cases and never overweight controls as well as families segregating extreme obesity and thinness. We first performed a GWAS on 520 cases (BMI>35 kg/m(2)) and 540 control subjects (BMI<25 kg/m(2)), on measures of obesity and obesity-related traits. We subsequently followed up obesity-associated signals by genotyping the top ∼500 SNPs from GWAS in the combined sample of cases, controls and family members totaling 2,256 individuals. For the binary trait of obesity, we found 16 genome-wide significant signals within the FTO gene (strongest signal at rs17817449, P = 2.5 × 10(-12)). We next examined obesity-related quantitative traits (such as total body weight, waist circumference and waist to hip ratio), and detected genome-wide significant signals between waist to hip ratio and NRXN3 (rs11624704, P = 2.67 × 10(-9)), previously associated with body weight and fat distribution. Our study demonstrated how a relatively small sample ascertained through extreme phenotypes can detect genuine associations in a GWAS.
The Genetic Architecture of Major Depressive Disorder in Han Chinese Women.
Roseann E Peterson, Na Cai, Tim B Bigdeli, Yihan Li, Mark Reimers, Anna Nikulova, Bradley T Webb, Silviu-Alin Bacanu, Brien P Riley, Jonathan Flint, Kenneth S Kendler
Despite the moderate, well-demonstrated heritability of major depressive disorder (MDD), there has been limited success in identifying replicable genetic risk loci, suggesting a complex genetic arc
hitecture. Research is needed to quantify the relative contribution of classes of genetic variation across the genome to inform future genetic studies of MDD.
Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
Andrew P Morris, Benjamin F Voight, Tanya M Teslovich, Teresa Ferreira, Ayellet V Segrè, Valgerdur Steinthorsdottir, Rona J Strawbridge, Hassan Khan, Harald Grallert, Anubha Mahajan, Inga Prokopenko, Hyun Min Kang, Christian Dina, Tonu Esko, Ross M Fraser, Stavroula Kanoni, Ashish Kumar, Vasiliki Lagou, Claudia Langenberg, Jian'an Luan, Cecilia M Lindgren, Martina Müller-Nurasyid, Sonali Pechlivanis, N William Rayner, Laura J Scott, Steven Wiltshire, Loic Yengo, Leena Kinnunen, Elizabeth J Rossin, Soumya Raychaudhuri, Andrew D Johnson, Antigone S Dimas, Ruth J F Loos, Sailaja Vedantam, Han Chen, Jose C Florez, Caroline Fox, Ching-Ti Liu, Denis Rybin, David J Couper, Wen Hong L Kao, Man Li, Marilyn C Cornelis, Peter Kraft, Qi Sun, Rob M van Dam, Heather M Stringham, Peter S Chines, Krista Fischer, Pierre Fontanillas, Oddgeir L Holmen, Sarah E Hunt, Anne U Jackson, Augustine Kong, Robert Lawrence, Julia Meyer, John R B Perry, Carl G P Platou, Simon Potter, Emil Rehnberg, Neil Robertson, Suthesh Sivapalaratnam, Alena Stančáková, Kathleen Stirrups, Gudmar Thorleifsson, Emmi Tikkanen, Andrew R Wood, Peter Almgren, Mustafa Atalay, Rafn Benediktsson, Lori L Bonnycastle, Noël Burtt, Jason Carey, Guillaume Charpentier, Andrew T Crenshaw, Alex S F Doney, Mozhgan Dorkhan, Sarah Edkins, Valur Emilsson, Elodie Eury, Tom Forsen, Karl Gertow, Bruna Gigante, George B Grant, Christopher J Groves, Candace Guiducci, Christian Herder, Astradur B Hreidarsson, Jennie Hui, Alan James, Anna Jonsson, Wolfgang Rathmann, Norman Klopp, Jasmina Kravic, Kaarel Krjutškov, Cordelia Langford, Karin Leander, Eero Lindholm, Stéphane Lobbens, Satu Männistö, Ghazala Mirza, Thomas W Mühleisen, Bill Musk, Melissa Parkin, Loukianos Rallidis, Jouko Saramies, Bengt Sennblad, Sonia Shah, Gunnar Sigurðsson, Angela Silveira, Gerald Steinbach, Barbara Thorand, Joseph Trakalo, Fabrizio Veglia, Roman Wennauer, Wendy Winckler, Delilah Zabaneh, Harry Campbell, Cornelia van Duijn, Andre G Uitterlinden, Albert Hofman, Eric Sijbrands, Goncalo R Abecasis, Katharine R Owen, Eleftheria Zeggini, Mieke D Trip, Nita G Forouhi, Ann-Christine Syvänen, Johan G Eriksson, Leena Peltonen, Markus M Nöthen, Beverley Balkau, Colin N A Palmer, Valeriya Lyssenko, Tiinamaija Tuomi, Bo Isomaa, David J Hunter, Lu Qi, None None, None None, None None, None None, None None, Alan R Shuldiner, Michael Roden, Ines Barroso, Tom Wilsgaard, John Beilby, Kees Hovingh, Jackie F Price, James F Wilson, Rainer Rauramaa, Timo A Lakka, Lars Lind, George Dedoussis, Inger Njølstad, Nancy L Pedersen, Kay-Tee Khaw, Nicholas J Wareham, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Eeva Korpi-Hyövälti, Juha Saltevo, Markku Laakso, Johanna Kuusisto, Andres Metspalu, Francis S Collins, Karen L Mohlke, Richard N Bergman, Jaakko Tuomilehto, Bernhard O Boehm, Christian Gieger, Kristian Hveem, Stephane Cauchi, Philippe Froguel, Damiano Baldassarre, Elena Tremoli, Steve E Humphries, Danish Saleheen, John Danesh, Erik Ingelsson, Samuli Ripatti, Veikko Salomaa, Raimund Erbel, Karl-Heinz Jöckel, Susanne Moebus, Annette Peters, Thomas Illig, Ulf de Faire, Anders Hamsten, Andrew D Morris, Peter J Donnelly, Timothy M Frayling, Andrew T Hattersley, Eric Boerwinkle, Olle Melander, Sekar Kathiresan, Peter M Nilsson, Panos Deloukas, Unnur Thorsteinsdottir, Leif C Groop, Kari Stefansson, Frank Hu, James S Pankow, Josée Dupuis, James B Meigs, David Altshuler, Michael Boehnke, Mark I McCarthy, None None
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,
981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.
HPA-axis multilocus genetic profile score moderates the association between maternal prenatal perceived stress and offspring depression in early adulthood.
Brooke G McKenna, Constance Hammen, Patricia A Brennan
Maternal stress during pregnancy can cause alterations to the fetal hypothalamus-pituitary-adrenal (HPA) axis, a phenomenon known as fetal programming that may have lasting effects on offspring out
comes, including depression. Evidence suggests that these effects may vary with respect to the offspring's genetic risk. Nonetheless, few studies have examined these effects into adulthood, when risk for depression onset is highest. The present study builds upon the extant literature by examining the interaction of maternal prenatal perceived stress (MPPS) and offspring HPA-axis polygenic risk to predict offspring depression in early adulthood. A total of 381 mother-child dyads participated in a prospective, longitudinal study that spanned from pregnancy until offspring were 20 years of age. Polygenic risk was defined by a multilocus genetic profile score (MGPS) that reflected the additive risk of three HPA-axis candidate genes. The results indicated that the interaction of MPPS and HPA-axis MGPS confers risk for offspring depression at age 20, in line with the differential susceptibility model. This interaction may be specific to prenatal stress, as maternal stress during early childhood did not interact with genetic risk to predict depression. These findings provide the first evidence that genetic variants that are associated with the HPA axis may act in a polygenic, additive fashion to moderate the association between fetal programming and adult depression.
A Genomewide Integrative Analysis of GWAS and eQTLs Data Identifies Multiple Genes and Gene Sets Associated with Obesity.
Li Liu, Qianrui Fan, Feng Zhang, Xiong Guo, Xiao Liang, Yanan Du, Ping Li, Yan Wen, Jingcan Hao, Wenyu Wang, Awen He
To identify novel susceptibility genes and gene sets for obesity, we conducted a genomewide expression association analysis of obesity via integrating genomewide association study (GWAS) and expres
sion quantitative trait loci (eQTLs) data. GWAS summary data of body mass index (BMI) and waist-to-hip ratio (WHR) was driven from a published study, totally involving 339,224 individuals. The eQTLs dataset (containing 927,753 eQTLs) was obtained from eQTLs meta-analysis of 5,311 subjects. Integrative analysis of GWAS and eQTLs data was conducted by SMR software. The SMR single gene analysis results were further subjected to gene set enrichment analysis (GSEA) for identifying obesity associated gene sets. A total of 13,311 annotated gene sets were analyzed in this study. SMR single gene analysis identified 20 BMI associated genes (
Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.
David M Howard, Mark J Adams, Toni-Kim Clarke, Jonathan D Hafferty, Jude Gibson, Masoud Shirali, Jonathan R I Coleman, Saskia P Hagenaars, Joey Ward, Eleanor M Wigmore, Clara Alloza, Xueyi Shen, Miruna C Barbu, Eileen Y Xu, Heather C Whalley, Riccardo E Marioni, David J Porteous, Gail Davies, Ian J Deary, Gibran Hemani, Klaus Berger, Henning Teismann, Rajesh Rawal, Volker Arolt, Bernhard T Baune, Udo Dannlowski, Katharina Domschke, Chao Tian, David A Hinds, None None, None None, Maciej Trzaskowski, Enda M Byrne, Stephan Ripke, Daniel J Smith, Patrick F Sullivan, Naomi R Wray, Gerome Breen, Cathryn M Lewis, Andrew M McIntosh
Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with c
urrent sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.
An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.
Nese Direk, Stephanie Williams, Jennifer A Smith, Stephan Ripke, Tracy Air, Azmeraw T Amare, Najaf Amin, Bernhard T Baune, David A Bennett, Douglas H R Blackwood, Dorret Boomsma, Gerome Breen, Henriette N Buttenschøn, Enda M Byrne, Anders D Børglum, Enrique Castelao, Sven Cichon, Toni-Kim Clarke, Marilyn C Cornelis, Udo Dannlowski, Philip L De Jager, Ayse Demirkan, Enrico Domenici, Cornelia M van Duijn, Erin C Dunn, Johan G Eriksson, Tonu Esko, Jessica D Faul, Luigi Ferrucci, Myriam Fornage, Eco de Geus, Michael Gill, Scott D Gordon, Hans Jörgen Grabe, Gerard van Grootheest, Steven P Hamilton, Catharina A Hartman, Andrew C Heath, Karin Hek, Albert Hofman, Georg Homuth, Carsten Horn, Jouke Jan Hottenga, Sharon L R Kardia, Stefan Kloiber, Karestan Koenen, Zoltán Kutalik, Karl-Heinz Ladwig, Jari Lahti, Douglas F Levinson, Cathryn M Lewis, Glyn Lewis, Qingqin S Li, David J Llewellyn, Susanne Lucae, Kathryn L Lunetta, Donald J MacIntyre, Pamela Madden, Nicholas G Martin, Andrew M McIntosh, Andres Metspalu, Yuri Milaneschi, Grant W Montgomery, Ole Mors, Thomas H Mosley, Joanne M Murabito, Bertram Müller-Myhsok, Markus M Nöthen, Dale R Nyholt, Michael C O'Donovan, Brenda W Penninx, Michele L Pergadia, Roy Perlis, James B Potash, Martin Preisig, Shaun M Purcell, Jorge A Quiroz, Katri Räikkönen, John P Rice, Marcella Rietschel, Margarita Rivera, Thomas G Schulze, Jianxin Shi, Stanley Shyn, Grant C Sinnamon, Johannes H Smit, Jordan W Smoller, Harold Snieder, Toshiko Tanaka, Katherine E Tansey, Alexander Teumer, Rudolf Uher, Daniel Umbricht, Sandra Van der Auwera, Erin B Ware, David R Weir, Myrna M Weissman, Gonneke Willemsen, Jingyun Yang, Wei Zhao, Henning Tiemeier, Patrick F Sullivan
The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depres
sion phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.
DNA methylation of methylation complex genes in relation to stress and genome-wide methylation in mother-newborn dyads.
Christopher J Clukay, David A Hughes, Nicole C Rodney, Darlene A Kertes, Connie J Mulligan
Early life stress is known to have enduring biological effects, particularly with respect to health. Epigenetic modifications, such as DNA methylation, are a possible mechanism to mediate the biolo
gical effect of stress. We previously found correlations between maternal stress, newborn birthweight, and genome-wide measures of DNA methylation. Here we investigate ten genes related to the methylation/demethylation complex in order to better understand the impact of stress on health.
Transcriptome alterations in maternal and fetal cells induced by tobacco smoke.
H Votavova, M Dostalova Merkerova, K Fejglova, A Vasikova, Z Krejcik, A Pastorkova, N Tabashidze, J Topinka, M Veleminsky, R J Sram, R Brdicka
Maternal smoking has a negative effect on all stages of pregnancy. Tobacco smoke-related defects are well established at the clinical level; however, less is known about molecular mechanisms underl
ying these pathologic conditions. We thus performed a comprehensive analysis of transcriptome alterations induced by smoking in maternal and fetal cells.
Genetic studies of body mass index yield new insights for obesity biology.
Adam E Locke, Bratati Kahali, Sonja I Berndt, Anne E Justice, Tune H Pers, Felix R Day, Corey Powell, Sailaja Vedantam, Martin L Buchkovich, Jian Yang, Damien C Croteau-Chonka, Tonu Esko, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Zoltán Kutalik, Jian'an Luan, Reedik Mägi, Joshua C Randall, Thomas W Winkler, Andrew R Wood, Tsegaselassie Workalemahu, Jessica D Faul, Jennifer A Smith, Jing Hua Zhao, Wei Zhao, Jin Chen, Rudolf Fehrmann, Åsa K Hedman, Juha Karjalainen, Ellen M Schmidt, Devin Absher, Najaf Amin, Denise Anderson, Marian Beekman, Jennifer L Bolton, Jennifer L Bragg-Gresham, Steven Buyske, Ayse Demirkan, Guohong Deng, Georg B Ehret, Bjarke Feenstra, Mary F Feitosa, Krista Fischer, Anuj Goel, Jian Gong, Anne U Jackson, Stavroula Kanoni, Marcus E Kleber, Kati Kristiansson, Unhee Lim, Vaneet Lotay, Massimo Mangino, Irene Mateo Leach, Carolina Medina-Gomez, Sarah E Medland, Michael A Nalls, Cameron D Palmer, Dorota Pasko, Sonali Pechlivanis, Marjolein J Peters, Inga Prokopenko, Dmitry Shungin, Alena Stančáková, Rona J Strawbridge, Yun Ju Sung, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sander W van der Laan, Jessica van Setten, Jana V Van Vliet-Ostaptchouk, Zhaoming Wang, Loïc Yengo, Weihua Zhang, Aaron Isaacs, Eva Albrecht, Johan Ärnlöv, Gillian M Arscott, Antony P Attwood, Stefania Bandinelli, Amy Barrett, Isabelita N Bas, Claire Bellis, Amanda J Bennett, Christian Berne, Roza Blagieva, Matthias Blüher, Stefan Böhringer, Lori L Bonnycastle, Yvonne Böttcher, Heather A Boyd, Marcel Bruinenberg, Ida H Caspersen, Yii-Der Ida Chen, Robert Clarke, E Warwick Daw, Anton J M de Craen, Graciela Delgado, Maria Dimitriou, Alex S F Doney, Niina Eklund, Karol Estrada, Elodie Eury, Lasse Folkersen, Ross M Fraser, Melissa E Garcia, Frank Geller, Vilmantas Giedraitis, Bruna Gigante, Alan S Go, Alain Golay, Alison H Goodall, Scott D Gordon, Mathias Gorski, Hans-Jörgen Grabe, Harald Grallert, Tanja B Grammer, Jürgen Gräßler, Henrik Grönberg, Christopher J Groves, Gaëlle Gusto, Jeffrey Haessler, Per Hall, Toomas Haller, Goran Hallmans, Catharina A Hartman, Maija Hassinen, Caroline Hayward, Nancy L Heard-Costa, Quinta Helmer, Christian Hengstenberg, Oddgeir Holmen, Jouke-Jan Hottenga, Alan L James, Janina M Jeff, Åsa Johansson, Jennifer Jolley, Thorhildur Juliusdottir, Leena Kinnunen, Wolfgang Koenig, Markku Koskenvuo, Wolfgang Kratzer, Jaana Laitinen, Claudia Lamina, Karin Leander, Nanette R Lee, Peter Lichtner, Lars Lind, Jaana Lindström, Ken Sin Lo, Stéphane Lobbens, Roberto Lorbeer, Yingchang Lu, François Mach, Patrik K E Magnusson, Anubha Mahajan, Wendy L McArdle, Stela McLachlan, Cristina Menni, Sigrun Merger, Evelin Mihailov, Lili Milani, Alireza Moayyeri, Keri L Monda, Mario A Morken, Antonella Mulas, Gabriele Müller, Martina Müller-Nurasyid, Arthur W Musk, Ramaiah Nagaraja, Markus M Nöthen, Ilja M Nolte, Stefan Pilz, Nigel W Rayner, Frida Renstrom, Rainer Rettig, Janina S Ried, Stephan Ripke, Neil R Robertson, Lynda M Rose, Serena Sanna, Hubert Scharnagl, Salome Scholtens, Fredrick R Schumacher, William R Scott, Thomas Seufferlein, Jianxin Shi, Albert Vernon Smith, Joanna Smolonska, Alice V Stanton, Valgerdur Steinthorsdottir, Kathleen Stirrups, Heather M Stringham, Johan Sundström, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Bamidele O Tayo, Barbara Thorand, Gudmar Thorleifsson, Jonathan P Tyrer, Hae-Won Uh, Liesbeth Vandenput, Frank C Verhulst, Sita H Vermeulen, Niek Verweij, Judith M Vonk, Lindsay L Waite, Helen R Warren, Dawn Waterworth, Michael N Weedon, Lynne R Wilkens, Christina Willenborg, Tom Wilsgaard, Mary K Wojczynski, Andrew Wong, Alan F Wright, Qunyuan Zhang, None None, Eoin P Brennan, Murim Choi, Zari Dastani, Alexander W Drong, Per Eriksson, Anders Franco-Cereceda, Jesper R Gådin, Ali G Gharavi, Michael E Goddard, Robert E Handsaker, Jinyan Huang, Fredrik Karpe, Sekar Kathiresan, Sarah Keildson, Krzysztof Kiryluk, Michiaki Kubo, Jong-Young Lee, Liming Liang, Richard P Lifton, Baoshan Ma, Steven A McCarroll, Amy J McKnight, Josine L Min, Miriam F Moffatt, Grant W Montgomery, Joanne M Murabito, George Nicholson, Dale R Nyholt, Yukinori Okada, John R B Perry, Rajkumar Dorajoo, Eva Reinmaa, Rany M Salem, Niina Sandholm, Robert A Scott, Lisette Stolk, Atsushi Takahashi, Toshihiro Tanaka, Ferdinand M van 't Hooft, Anna A E Vinkhuyzen, Harm-Jan Westra, Wei Zheng, Krina T Zondervan, None None, None None, None None, None None, None None, None None, None None, None None, None None, None None, None None, None None, None None, Andrew C Heath, Dominique Arveiler, Stephan J L Bakker, John Beilby, Richard N Bergman, John Blangero, Pascal Bovet, Harry Campbell, Mark J Caulfield, Giancarlo Cesana, Aravinda Chakravarti, Daniel I Chasman, Peter S Chines, Francis S Collins, Dana C Crawford, L Adrienne Cupples, Daniele Cusi, John Danesh, Ulf de Faire, Hester M den Ruijter, Anna F Dominiczak, Raimund Erbel, Jeanette Erdmann, Johan G Eriksson, Martin Farrall, Stephan B Felix, Ele Ferrannini, Jean Ferrières, Ian Ford, Nita G Forouhi, Terrence Forrester, Oscar H Franco, Ron T Gansevoort, Pablo V Gejman, Christian Gieger, Omri Gottesman, Vilmundur Gudnason, Ulf Gyllensten, Alistair S Hall, Tamara B Harris, Andrew T Hattersley, Andrew A Hicks, Lucia A Hindorff, Aroon D Hingorani, Albert Hofman, Georg Homuth, G Kees Hovingh, Steve E Humphries, Steven C Hunt, Elina Hyppönen, Thomas Illig, Kevin B Jacobs, Marjo-Riitta Jarvelin, Karl-Heinz Jöckel, Berit Johansen, Pekka Jousilahti, J Wouter Jukema, Antti M Jula, Jaakko Kaprio, John J P Kastelein, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Paul Knekt, Jaspal S Kooner, Charles Kooperberg, Peter Kovacs, Aldi T Kraja, Meena Kumari, Johanna Kuusisto, Timo A Lakka, Claudia Langenberg, Loic Le Marchand, Terho Lehtimäki, Valeriya Lyssenko, Satu Männistö, André Marette, Tara C Matise, Colin A McKenzie, Barbara McKnight, Frans L Moll, Andrew D Morris, Andrew P Morris, Jeffrey C Murray, Mari Nelis, Claes Ohlsson, Albertine J Oldehinkel, Ken K Ong, Pamela A F Madden, Gerard Pasterkamp, John F Peden, Annette Peters, Dirkje S Postma, Peter P Pramstaller, Jackie F Price, Lu Qi, Olli T Raitakari, Tuomo Rankinen, D C Rao, Treva K Rice, Paul M Ridker, John D Rioux, Marylyn D Ritchie, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Jouko Saramies, Mark A Sarzynski, Heribert Schunkert, Peter E H Schwarz, Peter Sever, Alan R Shuldiner, Juha Sinisalo, Ronald P Stolk, Konstantin Strauch, Anke Tönjes, David-Alexandre Trégouët, Angelo Tremblay, Elena Tremoli, Jarmo Virtamo, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Gonneke Willemsen, Jacqueline C Witteman, M Carola Zillikens, Linda S Adair, Philippe Amouyel, Folkert W Asselbergs, Themistocles L Assimes, Murielle Bochud, Bernhard O Boehm, Eric Boerwinkle, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, Stéphane Cauchi, John C Chambers, Stephen J Chanock, Richard S Cooper, Paul I W de Bakker, George Dedoussis, Luigi Ferrucci, Paul W Franks, Philippe Froguel, Leif C Groop, Christopher A Haiman, Anders Hamsten, Jennie Hui, David J Hunter, Kristian Hveem, Robert C Kaplan, Mika Kivimaki, Diana Kuh, Markku Laakso, Yongmei Liu, Nicholas G Martin, Winfried März, Mads Melbye, Andres Metspalu, Susanne Moebus, Patricia B Munroe, Inger Njølstad, Ben A Oostra, Colin N A Palmer, Nancy L Pedersen, Markus Perola, Louis Pérusse, Ulrike Peters, Chris Power, Thomas Quertermous, Rainer Rauramaa, Fernando Rivadeneira, Timo E Saaristo, Danish Saleheen, Naveed Sattar, Eric E Schadt, David Schlessinger, P Eline Slagboom, Harold Snieder, Tim D Spector, Unnur Thorsteinsdottir, Michael Stumvoll, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, Pim van der Harst, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, David R Weir, H-Erich Wichmann, James F Wilson, Pieter Zanen, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Iris M Heid, Jeffrey R O'Connell, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Lude Franke, Timothy M Frayling, Mark I McCarthy, Peter M Visscher, André Scherag, Cristen J Willer, Michael Boehnke, Karen L Mohlke, Cecilia M Lindgren, Jacques S Beckmann, Inês Barroso, Kari E North, Erik Ingelsson, Joel N Hirschhorn, Ruth J F Loos, Elizabeth K Speliotes
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass i
ndex (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
Identification of 15 genetic loci associated with risk of major depression in individuals of European descent.
Craig L Hyde, Michael W Nagle, Chao Tian, Xing Chen, Sara A Paciga, Jens R Wendland, Joyce Y Tung, David A Hinds, Roy H Perlis, Ashley R Winslow
Despite strong evidence supporting the heritability of major depressive disorder (MDD), previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used
self-report data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 individuals reporting no history of depression through 23andMe and carried out meta-analysis of these results with published MDD genome-wide association study results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with a P value <1.0 × 10(-5) in the meta-analysis were further analyzed in a replication data set (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint analysis over all three data sets. Some of these loci were also implicated in genome-wide association studies of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to data collected from traditional means of ascertainment for neuropsychiatric disease genomics.
A genome-wide association study of depressive symptoms.
Karin Hek, Ayse Demirkan, Jari Lahti, Antonio Terracciano, Alexander Teumer, Marilyn C Cornelis, Najaf Amin, Erin Bakshis, Jens Baumert, Jingzhong Ding, Yongmei Liu, Kristin Marciante, Osorio Meirelles, Michael A Nalls, Yan V Sun, Nicole Vogelzangs, Lei Yu, Stefania Bandinelli, Emelia J Benjamin, David A Bennett, Dorret Boomsma, Alessandra Cannas, Laura H Coker, Eco de Geus, Philip L De Jager, Ana V Diez-Roux, Shaun Purcell, Frank B Hu, Eric B Rimma, David J Hunter, Majken K Jensen, Gary Curhan, Kenneth Rice, Alan D Penman, Jerome I Rotter, Nona Sotoodehnia, Rebecca Emeny, Johan G Eriksson, Denis A Evans, Luigi Ferrucci, Myriam Fornage, Vilmundur Gudnason, Albert Hofman, Thomas Illig, Sharon Kardia, Margaret Kelly-Hayes, Karestan Koenen, Peter Kraft, Maris Kuningas, Joseph M Massaro, David Melzer, Antonella Mulas, Cornelis L Mulder, Anna Murray, Ben A Oostra, Aarno Palotie, Brenda Penninx, Astrid Petersmann, Luke C Pilling, Bruce Psaty, Rajesh Rawal, Eric M Reiman, Andrea Schulz, Joshua M Shulman, Andrew B Singleton, Albert V Smith, Angelina R Sutin, André G Uitterlinden, Henry Völzke, Elisabeth Widen, Kristine Yaffe, Alan B Zonderman, Francesco Cucca, Tamara Harris, Karl-Heinz Ladwig, David J Llewellyn, Katri Räikkönen, Toshiko Tanaka, Cornelia M van Duijn, Hans J Grabe, Lenore J Launer, Kathryn L Lunetta, Thomas H Mosley, Anne B Newman, Henning Tiemeier, Joanne Murabito
Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the en
tire continuum of depression to find common variants for depressive symptoms.
Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank.
Jonathan R I Coleman, Wouter J Peyrot, Kirstin L Purves, Katrina A S Davis, Christopher Rayner, Shing Wan Choi, Christopher Hübel, Héléna A Gaspar, Carol Kan, Sandra Van der Auwera, Mark James Adams, Donald M Lyall, Karmel W Choi, None None, Erin C Dunn, Evangelos Vassos, Andrea Danese, Barbara Maughan, Hans J Grabe, Cathryn M Lewis, Paul F O'Reilly, Andrew M McIntosh, Daniel J Smith, Naomi R Wray, Matthew Hotopf, Thalia C Eley, Gerome Breen
Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of g
enetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (r
Sparse whole-genome sequencing identifies two loci for major depressive disorder.
Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide, poses a major challenge to genetic analysis. To date, no
robustly replicated genetic loci have been identified, despite analysis of more than 9,000 cases. Here, using low-coverage whole-genome sequencing of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified, and subsequently replicated in an independent sample, two loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P = 2.53 × 10(-10)), the other in an intron of the LHPP gene (P = 6.45 × 10(-12)). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.
DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm.
Lei Cao-Lei, Renaud Massart, Matthew J Suderman, Ziv Machnes, Guillaume Elgbeili, David P Laplante, Moshe Szyf, Suzanne King
Prenatal maternal stress (PNMS) predicts a wide variety of behavioral and physical outcomes in the offspring. Although epigenetic processes may be responsible for PNMS effects, human research is ha
mpered by the lack of experimental methods that parallel controlled animal studies. Disasters, however, provide natural experiments that can provide models of prenatal stress.
Deregulation of gene expression induced by environmental tobacco smoke exposure in pregnancy.
Hana Votavova, Michaela Dostalova Merkerova, Zdenek Krejcik, Kamila Fejglova, Alzbeta Vasikova, Anna Pastorkova, Nana Tabashidze, Jan Topinka, Ivan Balascak, Radim J Sram, Radim Brdicka
Environmental tobacco smoke (ETS) exposure in pregnant women may have detrimental effects such as spontaneous abortion, lower birth weight, stillbirth, and reduced infant lung function. To extend o
ur knowledge on the molecular effects of tobacco smoke exposure in pregnancy, we analyzed transcriptome alterations in passive smokers (PS) and compared them with those in active smokers (AS).
Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes.
Michael S Breen, Aliza P Wingo, Nastassja Koen, Kirsten A Donald, Mark Nicol, Heather J Zar, Kerry J Ressler, Joseph D Buxbaum, Dan J Stein
Prenatal exposure to maternal stress and depression has been identified as a risk factor for adverse behavioral and neurodevelopmental outcomes in early childhood. However, the molecular mechanisms
through which maternal psychopathology shapes offspring development remain poorly understood. We applied transcriptome-wide screens to 149 umbilical cord blood samples from neonates born to mothers with posttraumatic stress disorder (PTSD; n = 20), depression (n = 31) and PTSD with comorbid depression (n = 13), compared to carefully matched trauma exposed controls (n = 23) and healthy mothers (n = 62). Analyses by maternal diagnoses revealed a clear pattern of gene expression signatures distinguishing neonates born to mothers with a history of psychopathology from those without. Co-expression network analysis identified distinct gene expression perturbations across maternal diagnoses, including two depression-related modules implicated in axon-guidance and mRNA stability, as well as two PTSD-related modules implicated in TNF signaling and cellular response to stress. Notably, these disease-related modules were enriched with brain-expressed genes and genetic risk loci for autism spectrum disorder and schizophrenia, which may imply a causal role for impaired developmental outcomes. These molecular alterations preceded changes in clinical measures at twenty-four months, including reductions in cognitive and socio-emotional outcomes in affected infants. Collectively, these findings indicate that prenatal exposure to maternal psychological distress induces neuronal, immunological and behavioral abnormalities in affected offspring and support the search for early biomarkers of exposures to adverse in utero environments and the classification of children at risk for impaired development.
Primate fetal hepatic responses to maternal obesity: epigenetic signalling pathways and lipid accumulation.
Sobha Puppala, Cun Li, Jeremy P Glenn, Romil Saxena, Samer Gawrieh, Amy Quinn, Jennifer Palarczyk, Edward J Dick, Peter W Nathanielsz, Laura A Cox
Maternal obesity (MO) and exposure to a high-fat, high-simple-carbohydrate diet during pregnancy predisposes offspring to obesity, metabolic and cardiovascular disorders in later life. Underlying m
olecular pathways and potential epigenetic factors that are dysregulated in MO were identified using unbiased transcriptomic methods. There was increased lipid accumulation and severe steatosis in the MO baboon fetal liver suggesting that these offspring are on an early trajectory of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
Circulating miRNA associated with posttraumatic stress disorder in a cohort of military combat veterans.
Christiana G Martin, Hyungsuk Kim, Sijung Yun, Whitney Livingston, Joseph Fetta, Vincent Mysliwiec, Tristin Baxter, Jessica M Gill
Posttraumatic stress disorder (PTSD) affects many returning combat veterans, but underlying biological mechanisms remain unclear. In order to compare circulating micro RNA (miRNA) of combat veteran
s with and without PTSD, peripheral blood from 24 subjects was collected following deployment, and isolated miRNA was sequenced. PTSD was associated with 8 differentially expressed miRNA. Pathway analysis shows that PTSD is related to the axon guidance and Wnt signaling pathways, which work together to support neuronal development through regulation of growth cones. PTSD is associated with miRNAs that regulate biological functions including neuronal activities, suggesting that they play a role in PTSD symptomatology.
Integrative network analysis reveals biological pathways associated with Williams syndrome.
Ryo Kimura, Vivek Swarup, Kiyotaka Tomiwa, Michael J Gandal, Neelroop N Parikshak, Yasuko Funabiki, Masatoshi Nakata, Tomonari Awaya, Takeo Kato, Kei Iida, Shin Okazaki, Kanae Matsushima, Toshihiro Kato, Toshiya Murai, Toshio Heike, Daniel H Geschwind, Masatoshi Hagiwara
Williams syndrome (WS) is a neurodevelopmental disorder that has been attributed to heterozygous deletions in chromosome 7q11.23 and exhibits a variety of physical, cognitive, and behavioral featur
es. However, the genetic basis of this phenotypic variability is unclear. In this study, we identified genetic clues underlying these complex phenotypes.
DNA methylation signature of human fetal alcohol spectrum disorder.
Elodie Portales-Casamar, Alexandre A Lussier, Meaghan J Jones, Julia L MacIsaac, Rachel D Edgar, Sarah M Mah, Amina Barhdadi, Sylvie Provost, Louis-Philippe Lemieux-Perreault, Max S Cynader, Albert E Chudley, Marie-Pierre Dubé, James N Reynolds, Paul Pavlidis, Michael S Kobor
Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of
alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date.
The effects of alcoholism on the human basolateral amygdala.
R Kryger, P A Wilce
Alcohol affects gene expression in several brain regions. The amygdala is a key structure in the brain's emotional system and in recent years the crucial importance of the amygdala in drug-seeking
and relapse has been increasingly recognized. In this study gene expression screening was used to identify genes involved in alcoholism in the human basolateral amygdala of male patients. The results show that alcoholism affects a broad range of genes and many systems including genes involved in synaptic transmission, neurotransmitter transport, structural plasticity, metabolism, energy production, transcription and RNA processing and the circadian cycle. In particular, genes involved in the glutamate system were affected in the alcoholic patients. In the amygdala the glutamate system is involved in the acquisition, consolidation, expression and extinction of associative learning, which is a vital part of addiction, and in alcohol abusers it is associated with withdrawal anxiety and neurodegeneration. Downregulation of the excitatory amino acid transporters GLAST, GLT-1 and the AMPA glutamate receptor 2 (GluR2) revealed by the microarray were confirmed by Western blots. The decreased expression of GLAST, GLT-1 and GluR2 in the alcoholic patients may increase glutamate tone and activity in the basolateral amygdala and this may contribute to neurodegeneration as well as the expression of associative memories and anxiety which underlie continued drug-seeking and chronic relapse.
The Dunedin Multidisciplinary Health and Development Study: overview of the first 40 years, with an eye to the future.
Richie Poulton, Terrie E Moffitt, Phil A Silva
The Dunedin Multidisciplinary Health and Development Study began more than four decades ago. Unusual at the time, it was founded as a multidisciplinary research enterprise, and was strongly support
ed by the Dunedin community, both professional and lay, in its early years. Seven research themes have evolved over the past 40 years focusing on mental health and neuro-cognition, cardiovascular risk, respiratory health, oral health, sexual and reproductive health, and psychosocial functioning. A seventh, more applied theme, seeks to maximise the value of the Study findings for New Zealand's indigenous people-Māori (or tangata whenua transl people of the land). The study has published over 1200 papers and reports to date, with almost 2/3 of these being in peer-reviewed journals. Here we provide an overview of the study, its history, leadership structure, scientific approach, operational foci, and some recent examples of work that illustrate the following: (a) the value of multidisciplinary data; (b) how the study is well positioned to address contemporary issues; and (c) how research can simultaneously address multiple audiences-from researchers and theoreticians to policy makers and practitioners. Near-future research plans are described, and we end by reflecting upon the core aspects of the study that portend future useful contributions.
ZeitZeiger: supervised learning for high-dimensional data from an oscillatory system.
Jacob J Hughey, Trevor Hastie, Atul J Butte
Numerous biological systems oscillate over time or space. Despite these oscillators' importance, data from an oscillatory system is problematic for existing methods of regularized supervised learni
ng. We present ZeitZeiger, a method to predict a periodic variable (e.g. time of day) from a high-dimensional observation. ZeitZeiger learns a sparse representation of the variation associated with the periodic variable in the training observations, then uses maximum-likelihood to make a prediction for a test observation. We applied ZeitZeiger to a comprehensive dataset of genome-wide gene expression from the mammalian circadian oscillator. Using the expression of 13 genes, ZeitZeiger predicted circadian time (internal time of day) in each of 12 mouse organs to within ∼1 h, resulting in a multi-organ predictor of circadian time. Compared to the state-of-the-art approach, ZeitZeiger was faster, more accurate and used fewer genes. We then validated the multi-organ predictor on 20 additional datasets comprising nearly 800 samples. Our results suggest that ZeitZeiger not only makes accurate predictions, but also gives insight into the behavior and structure of the oscillator from which the data originated. As our ability to collect high-dimensional data from various biological oscillators increases, ZeitZeiger should enhance efforts to convert these data to knowledge.
Childhood maltreatment predicts adult inflammation in a life-course study.
Andrea Danese, Carmine M Pariante, Avshalom Caspi, Alan Taylor, Richie Poulton
Stress in early life has been associated with insufficient glucocorticoid signaling in adulthood, possibly affecting inflammation processes. Childhood maltreatment has been linked to increased risk
of adult disease with potential inflammatory origin. However, the impact of early life stress on adult inflammation is not known in humans. We tested the life-course association between childhood maltreatment and adult inflammation in a birth cohort followed to age 32 years as part of the Dunedin Multidisciplinary Health and Development Study. Regression models were used to estimate the effect of maltreatment on inflammation, adjusting for co-occurring risk factors and potential mediating variables. Maltreated children showed a significant and graded increase in the risk for clinically relevant C-reactive protein levels 20 years later, in adulthood [risk ratio (RR)=1.80, 95% confidence interval (CI)=1.26-2.58]. The effect of childhood maltreatment on adult inflammation was independent of the influence of co-occurring early life risks (RR=1.58, 95% CI=1.08-2.31), stress in adulthood (RR=1.64, 95% CI=1.12-2.39), and adult health and health behavior (RR=1.76, 95% CI=1.23-2.51). More than 10% of cases of low-grade inflammation in the population, as indexed by high C-reactive protein, may be attributable to childhood maltreatment. The association between maltreatment and adult inflammation also generalizes to fibrinogen and white blood cell count. Childhood maltreatment is a previously undescribed, independent, and preventable risk factor for inflammation in adulthood. Inflammation may be an important developmental mediator linking adverse experiences in early life to poor adult health.
Machine learning identifies a compact gene set for monitoring the circadian clock in human blood.
Jacob J Hughey
The circadian clock and the daily rhythms it produces are crucial for human health, but are often disrupted by the modern environment. At the same time, circadian rhythms may influence the efficacy
and toxicity of therapeutics and the metabolic response to food intake. Developing treatments for circadian dysfunction, as well as optimizing the daily timing of treatments for other health conditions, will require a simple and accurate method to monitor the molecular state of the circadian clock.
Mistimed sleep disrupts circadian regulation of the human transcriptome.
Simon N Archer, Emma E Laing, Carla S Möller-Levet, Daan R van der Veen, Giselda Bucca, Alpar S Lazar, Nayantara Santhi, Ana Slak, Renata Kabiljo, Malcolm von Schantz, Colin P Smith, Derk-Jan Dijk
Circadian organization of the mammalian transcriptome is achieved by rhythmic recruitment of key modifiers of chromatin structure and transcriptional and translational processes. These rhythmic pro
cesses, together with posttranslational modification, constitute circadian oscillators in the brain and peripheral tissues, which drive rhythms in physiology and behavior, including the sleep-wake cycle. In humans, sleep is normally timed to occur during the biological night, when body temperature is low and melatonin is synthesized. Desynchrony of sleep-wake timing and other circadian rhythms, such as occurs in shift work and jet lag, is associated with disruption of rhythmicity in physiology and endocrinology. However, to what extent mistimed sleep affects the molecular regulators of circadian rhythmicity remains to be established. Here, we show that mistimed sleep leads to a reduction of rhythmic transcripts in the human blood transcriptome from 6.4% at baseline to 1.0% during forced desynchrony of sleep and centrally driven circadian rhythms. Transcripts affected are key regulators of gene expression, including those associated with chromatin modification (methylases and acetylases), transcription (RNA polymerase II), translation (ribosomal proteins, initiation, and elongation factors), temperature-regulated transcription (cold inducible RNA-binding proteins), and core clock genes including CLOCK and ARNTL (BMAL1). We also estimated the separate contribution of sleep and circadian rhythmicity and found that the sleep-wake cycle coordinates the timing of transcription and translation in particular. The data show that mistimed sleep affects molecular processes at the core of circadian rhythm generation and imply that appropriate timing of sleep contributes significantly to the overall temporal organization of the human transcriptome.
Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome.
Carla S Möller-Levet, Simon N Archer, Giselda Bucca, Emma E Laing, Ana Slak, Renata Kabiljo, June C Y Lo, Nayantara Santhi, Malcolm von Schantz, Colin P Smith, Derk-Jan Dijk
Insufficient sleep and circadian rhythm disruption are associated with negative health outcomes, including obesity, cardiovascular disease, and cognitive impairment, but the mechanisms involved rem
ain largely unexplored. Twenty-six participants were exposed to 1 wk of insufficient sleep (sleep-restriction condition 5.70 h, SEM = 0.03 sleep per 24 h) and 1 wk of sufficient sleep (control condition 8.50 h sleep, SEM = 0.11). Immediately following each condition, 10 whole-blood RNA samples were collected from each participant, while controlling for the effects of light, activity, and food, during a period of total sleep deprivation. Transcriptome analysis revealed that 711 genes were up- or down-regulated by insufficient sleep. Insufficient sleep also reduced the number of genes with a circadian expression profile from 1,855 to 1,481, reduced the circadian amplitude of these genes, and led to an increase in the number of genes that responded to subsequent total sleep deprivation from 122 to 856. Genes affected by insufficient sleep were associated with circadian rhythms (PER1, PER2, PER3, CRY2, CLOCK, NR1D1, NR1D2, RORA, DEC1, CSNK1E), sleep homeostasis (IL6, STAT3, KCNV2, CAMK2D), oxidative stress (PRDX2, PRDX5), and metabolism (SLC2A3, SLC2A5, GHRL, ABCA1). Biological processes affected included chromatin modification, gene-expression regulation, macromolecular metabolism, and inflammatory, immune and stress responses. Thus, insufficient sleep affects the human blood transcriptome, disrupts its circadian regulation, and intensifies the effects of acute total sleep deprivation. The identified biological processes may be involved with the negative effects of sleep loss on health, and highlight the interrelatedness of sleep homeostasis, circadian rhythmicity, and metabolism.
Antenatal prediction of postpartum depression with blood DNA methylation biomarkers.
J Guintivano, M Arad, T D Gould, J L Payne, Z A Kaminsky
Postpartum depression (PPD) affects ∼10-18% of women in the general population and results in serious consequences to both the mother and offspring. We hypothesized that predisposition to PPD risk
is due to an altered sensitivity to estrogen-mediated epigenetic changes that act in a cell autonomous manner detectable in the blood. We investigated estrogen-mediated epigenetic reprogramming events in the hippocampus and risk to PPD using a cross-species translational design. DNA methylation profiles were generated using methylation microarrays in a prospective sample of the blood from the antenatal period of pregnant mood disorder patients who would and would not develop depression postpartum. These profiles were cross-referenced with syntenic locations exhibiting hippocampal DNA methylation changes in the mouse responsive to long-term treatment with 17β-estradiol (E2). DNA methylation associated with PPD risk correlated significantly with E2-induced DNA methylation change, suggesting an enhanced sensitivity to estrogen-based DNA methylation reprogramming exists in those at risk for PPD. Using the combined mouse and human data, we identified two biomarker loci at the HP1BP3 and TTC9B genes that predicted PPD with an area under the receiver operator characteristic (ROC) curve (area under the curve (AUC)) of 0.87 in antenatally euthymic women and 0.12 in a replication sample of antenatally depressed women. Incorporation of blood count data into the model accounted for the discrepancy and produced an AUC of 0.96 across both prepartum depressed and euthymic women. Pathway analyses demonstrated that DNA methylation patterns related to hippocampal synaptic plasticity may be of etiological importance to PPD.
Microarray profiling and co-expression network analysis of circulating lncRNAs and mRNAs associated with major depressive disorder.
Zhifen Liu, Xinrong Li, Ning Sun, Yong Xu, Yaqin Meng, Chunxia Yang, Yanfang Wang, Kerang Zhang
LncRNAs, which represent one of the most highly expressed classes of ncRNAs in the brain, are becoming increasingly interesting with regard to brain functions and disorders. However, changes in the
expression of regulatory lncRNAs in Major Depressive Disorder (MDD) have not yet been reported. Using microarrays, we profiled the expression of 34834 lncRNAs and 39224 mRNAs in peripheral blood sampled from MDD patients as well as demographically-matched controls. Among these, we found that 2007 lncRNAs and 1667 mRNAs were differentially expressed, 17 of which were documented as depression-related gene in previous studies. Gene Ontology (GO) and pathway analyses indicated that the biological functions of differentially expressed mRNAs were related to fundamental metabolic processes and neurodevelopment diseases. To investigate the potential regulatory roles of the differentially expressed lncRNAs on the mRNAs, we also constructed co-expression networks composed of the lncRNAs and mRNAs, which shows significant correlated patterns of expression. In the MDD-derived network, there were a greater number of nodes and connections than that in the control-derived network. The lncRNAs located at chr10:874695-874794, chr10:75873456-75873642, and chr3:47048304-47048512 may be important factors regulating the expression of mRNAs as they have previously been reported associations with MDD. This study is the first to explore genome-wide lncRNA expression and co-expression with mRNA patterns in MDD using microarray technology. We identified circulating lncRNAs that are aberrantly expressed in MDD and the results suggest that lncRNAs may contribute to the molecular pathogenesis of MDD.
Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.
T M Murphy, B Crawford, E L Dempster, E Hannon, J Burrage, G Turecki, Z Kaminsky, J Mill
Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly un
derstood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.
Stimulated gene expression profiles as a blood marker of major depressive disorder.
Sabine Spijker, Jeroen S Van Zanten, Simone De Jong, Brenda W J H Penninx, Richard van Dyck, Frans G Zitman, Jan H Smit, Bauke Ylstra, August B Smit, Witte J G Hoogendijk
Major depressive disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available.
Prenatal risk factors and neonatal DNA methylation in very preterm infants.
Marie Camerota, Stefan Graw, Todd M Everson, Elisabeth C McGowan, Julie A Hofheimer, T Michael O'Shea, Brian S Carter, Jennifer B Helderman, Jennifer Check, Charles R Neal, Steven L Pastyrnak, Lynne M Smith, Lynne M Dansereau, Sheri A DellaGrotta, Carmen J Marsit, Barry M Lester
Prenatal risk factors are related to poor health and developmental outcomes for infants, potentially via epigenetic mechanisms. We tested associations between person-centered prenatal risk profiles
, cumulative prenatal risk models, and epigenome-wide DNA methylation (DNAm) in very preterm neonates.
Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
R Belzeaux, A Bergon, V Jeanjean, B Loriod, C Formisano-Tréziny, L Verrier, A Loundou, K Baumstarck-Barrau, L Boyer, V Gall, J Gabert, C Nguyen, J-M Azorin, J Naudin, E C Ibrahim
To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measur
ements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs (PPT1, TNF, IL1B and HIST1H1E) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis.
Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders.
K Iwamoto, C Kakiuchi, M Bundo, K Ikeda, T Kato
We performed the oligonucleotide microarray analysis in bipolar disorder, major depression, schizophrenia, and control subjects using postmortem prefrontal cortices provided by the Stanley Foundati
on Brain Collection. By comparing the gene expression profiles of similar but distinctive mental disorders, we explored the uniqueness of bipolar disorder and its similarity to other mental disorders at the molecular level. Notably, most of the altered gene expressions in each disease were not shared by one another, suggesting the molecular distinctiveness of these mental disorders. We found a tendency of downregulation of the genes encoding receptor, channels or transporters, and upregulation of the genes encoding stress response proteins or molecular chaperons in bipolar disorder. Altered expressions in bipolar disorder shared by other mental disorders mainly consisted of upregulation of the genes encoding proteins for transcription or translation. The genes identified in this study would be useful for the understanding of the pathophysiology of bipolar disorder, as well as the common pathophysiological background in major mental disorders at the molecular level. In addition, we found the altered expression of LIM and HSPF1 both in the brains and lymphoblastoid cells in bipolar disorder. These genes may have pathophysiological importance and would be novel candidate genes for bipolar disorder.
Circadian patterns of gene expression in the human brain and disruption in major depressive disorder.
Jun Z Li, Blynn G Bunney, Fan Meng, Megan H Hagenauer, David M Walsh, Marquis P Vawter, Simon J Evans, Prabhakara V Choudary, Preston Cartagena, Jack D Barchas, Alan F Schatzberg, Edward G Jones, Richard M Myers, Stanley J Watson, Huda Akil, William E Bunney
A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patien
ts who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses ("controls") and 34 patients with MDD. Our dataset covered ~12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERBa), DBP, BHLHE40 (DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders.
A negative regulator of MAP kinase causes depressive behavior.
Vanja Duric, Mounira Banasr, Pawel Licznerski, Heath D Schmidt, Craig A Stockmeier, Arthur A Simen, Samuel S Newton, Ronald S Duman
The lifetime prevalence (∼16%) and the economic burden ($100 billion annually) associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnes
ses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade, a major signaling pathway involved in neuronal plasticity, function and survival. We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions.
Methylation marks of prenatal exposure to maternal smoking and risk of cancer in adulthood.
Pierre-Antoine Dugué, Allison M Hodge, Ee Ming Wong, JiHoon E Joo, Chol-Hee Jung, John L Hopper, Dallas R English, Graham G Giles, Roger L Milne, Melissa C Southey
Prenatal exposure to maternal smoking is detrimental to child health but its association with risk of cancer has seldom been investigated. Maternal smoking induces widespread and long-lasting DNA m
ethylation changes, which we study here for association with risk of cancer in adulthood.
A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies.
Lun-Ching Chang, Stephane Jamain, Chien-Wei Lin, Dan Rujescu, George C Tseng, Etienne Sibille
Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related
information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases. In support of the superior discriminative power of this novel approach, we observed no significant enrichment for GWAS-related genes in coexpression modules extracted from single studies or in meta-modules using gene expression data from non-psychiatric control subjects. Genes in the identified module encode proteins implicated in neuronal signaling and structure, including glutamate metabotropic receptors (GRM1, GRM7), GABA receptors (GABRA2, GABRA4), and neurotrophic and development-related proteins [BDNF, reelin (RELN), Ephrin receptors (EPHA3, EPHA5)]. These results are consistent with the current understanding of molecular mechanisms of MDD and provide a set of putative interacting molecular partners, potentially reflecting components of a functional module across cells and biological pathways that are synchronously recruited in MDD, other brain disorders and MDD-related illnesses. Collectively, this study demonstrates the importance of integrating transcriptome data, gene coexpression modules and GWAS results for providing novel and complementary approaches to investigate the molecular pathology of MDD and other complex brain disorders.
Epigenetics of early-life adversity in youth: cross-sectional and longitudinal associations.
Jennifer A Sumner, Simone Gambazza, Xu Gao, Andrea A Baccarelli, Monica Uddin, Katie A McLaughlin
Altered DNA methylation (DNAm) may be one pathway through which early-life adversity (ELA) contributes to adverse mental and physical health outcomes. This study investigated whether the presence v
ersus absence of ELA experiences reflecting the dimensions of threat and deprivation were associated with epigenome-wide DNAm cross-sectionally and longitudinally in a community-based sample of children and adolescents.
DNA methylation in stress and depression: from biomarker to therapeutics.
Amanda J Sales, Francisco S Guimarães, Sâmia R L Joca
Epigenetic mechanisms such as DNA methylation (DNAm) have been associated with stress responses and increased vulnerability to depression. Abnormal DNAm is observed in stressed animals and depresse
d individuals. Antidepressant treatment modulates DNAm levels and regulates gene expression in diverse tissues, including the brain and the blood. Therefore, DNAm could be a potential therapeutic target in depression. Here, we reviewed the current knowledge about the involvement of DNAm in the behavioural and molecular changes associated with stress exposure and depression. We also evaluated the possible use of DNAm changes as biomarkers of depression. Finally, we discussed current knowledge limitations and future perspectives.
Sex- and tissue-specific effects of binge-level prenatal alcohol consumption on DNA methylation at birth.
Yuk Jing Loke, Evelyne Muggli, Richard Saffery, Joanne Ryan, Sharon Lewis, Elizabeth J Elliott, Jane Halliday, Jeffrey M Craig
Epigenetic prediction of major depressive disorder.
Miruna C Barbu, Xueyi Shen, Rosie M Walker, David M Howard, Kathryn L Evans, Heather C Whalley, David J Porteous, Stewart W Morris, Ian J Deary, Yanni Zeng, Riccardo E Marioni, Toni-Kim Clarke, Andrew M McIntosh
Variation in DNA methylation (DNAm) is associated with lifestyle factors such as smoking and body mass index (BMI) but there has been little research exploring its ability to identify individuals w
ith major depressive disorder (MDD). Using penalised regression on genome-wide CpG methylation, we tested whether DNAm risk scores (MRS), trained on 1223 MDD cases and 1824 controls, could discriminate between cases (n = 363) and controls (n = 1417) in an independent sample, comparing their predictive accuracy to polygenic risk scores (PRS). The MRS explained 1.75% of the variance in MDD (β = 0.338, p = 1.17 × 10
Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.
Gemma C Sharp, Lucas A Salas, Claire Monnereau, Catherine Allard, Paul Yousefi, Todd M Everson, Jon Bohlin, Zongli Xu, Rae-Chi Huang, Sarah E Reese, Cheng-Jian Xu, Nour Baïz, Cathrine Hoyo, Golareh Agha, Ritu Roy, John W Holloway, Akram Ghantous, Simon K Merid, Kelly M Bakulski, Leanne K Küpers, Hongmei Zhang, Rebecca C Richmond, Christian M Page, Liesbeth Duijts, Rolv T Lie, Phillip E Melton, Judith M Vonk, Ellen A Nohr, ClarLynda Williams-DeVane, Karen Huen, Sheryl L Rifas-Shiman, Carlos Ruiz-Arenas, Semira Gonseth, Faisal I Rezwan, Zdenko Herceg, Sandra Ekström, Lisa Croen, Fahimeh Falahi, Patrice Perron, Margaret R Karagas, Bilal M Quraishi, Matthew Suderman, Maria C Magnus, Vincent W V Jaddoe, Jack A Taylor, Denise Anderson, Shanshan Zhao, Henriette A Smit, Michele J Josey, Asa Bradman, Andrea A Baccarelli, Mariona Bustamante, Siri E Håberg, Göran Pershagen, Irva Hertz-Picciotto, Craig Newschaffer, Eva Corpeleijn, Luigi Bouchard, Debbie A Lawlor, Rachel L Maguire, Lisa F Barcellos, George Davey Smith, Brenda Eskenazi, Wilfried Karmaus, Carmen J Marsit, Marie-France Hivert, Harold Snieder, M Daniele Fallin, Erik Melén, Monica C Munthe-Kaas, Hasan Arshad, Joseph L Wiemels, Isabella Annesi-Maesano, Martine Vrijheid, Emily Oken, Nina Holland, Susan K Murphy, Thorkild I A Sørensen, Gerard H Koppelman, John P Newnham, Allen J Wilcox, Wenche Nystad, Stephanie J London, Janine F Felix, Caroline L Relton
Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could co
ntribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.
Prenatal nicotine exposure leads to decreased histone H3 lysine 9 (H3K9) methylation and increased
Sergio Raez-Villanueva, Amrita Debnath, Daniel B Hardy, Alison C Holloway
Prenatal exposure to nicotine, tobacco's major addictive constituent, has been shown to reduce birth weight and increases apoptosis, oxidative stress, and mitochondrial dysfunction in the postnatal
pancreas. Given that upregulated levels of the pro-oxidative adapter protein p66shc is observed in growth-restricted offspring and is linked to beta-cell apoptosis, the goal of this study was to investigate whether alterations in p66shc expression underlie the pancreatic deficits in nicotine-exposed offspring. Maternal administration of nicotine in rats increased p66shc expression in the neonatal pancreas. Similarly, nicotine treatment augmented p66shc expression in INS-1E pancreatic beta cells. Increased p66shc expression was also associated with decreased histone H3 lysine 9 methylation. Finally, nicotine increased the expression of Kdm4c, a key histone lysine demethylase, and decreased Suv39h1, a critical histone lysine methyltransferase. Collectively, these results suggest that upregulation of p66shc through posttranslational histone modifications may underlie the reported adverse outcomes of nicotine exposure on pancreatic function.
DNA methylation at birth potentially mediates the association between prenatal lead (Pb) exposure and infant neurodevelopmental outcomes.
Christine A Rygiel, Dana C Dolinoy, Kelly M Bakulski, Max T Aung, Wei Perng, Tamara R Jones, Maritsa Solano-González, Howard Hu, Martha M Tellez-Rojo, Lourdes Schnaas, Erika Marcela, Karen E Peterson, Jaclyn M Goodrich
Early-life lead (Pb) exposure has been linked to adverse neurodevelopmental outcomes. Recent evidence has indicated a critical role of DNA methylation (DNAm) in cognition, and Pb exposure has also
been shown to alter DNAm. However, it is unknown whether DNAm is part of the mechanism of Pb neurotoxicity. This longitudinal study investigated the associations between trimester-specific (T1, T2, and T3) maternal blood Pb concentrations, gene-specific DNAm in umbilical cord blood, and infant neurodevelopmental outcomes at 12 and 24 months of age (mental development index, psychomotor development index, and behavioral rating scale of orientation/engagement and emotional regulation) among 85 mother-infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study. In the mediation analysis for this pilot study,
Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals.
Anne K Bozack, Sheryl L Rifas-Shiman, Brent A Coull, Andrea A Baccarelli, Robert O Wright, Chitra Amarasiriwardena, Diane R Gold, Emily Oken, Marie-France Hivert, Andres Cardenas
Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prena
tal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses.
Intergenerational effects of maternal post-traumatic stress disorder on offspring epigenetic patterns and cortisol levels.
Line Hjort, Feride Rushiti, Shr-Jie Wang, Peter Fransquet, Sebahate P Krasniqi, Selvi I Çarkaxhiu, Dafina Arifaj, Vjosa Devaja Xhemaili, Mimoza Salihu, Nazmie A Leku, Joanne Ryan
Prenatal Air Pollution Exposure and Placental DNA Methylation Changes: Implications on Fetal Development and Future Disease Susceptibility.
Terisha Ghazi, Pragalathan Naidoo, Rajen N Naidoo, Anil A Chuturgoon
The Developmental Origins of Health and Disease (DOHaD) concept postulates that in utero exposures influence fetal programming and health in later life. Throughout pregnancy, the placenta plays a c
entral role in fetal programming; it regulates the in utero environment and acts as a gatekeeper for nutrient and waste exchange between the mother and the fetus. Maternal exposure to air pollution, including heavy metals, can reach the placenta, where they alter DNA methylation patterns, leading to changes in placental function and fetal reprogramming. This review explores the current knowledge on placental DNA methylation changes associated with prenatal air pollution (including heavy metals) exposure and highlights its effects on fetal development and disease susceptibility. Prenatal exposure to air pollution and heavy metals was associated with altered placental DNA methylation at the global and promoter regions of genes involved in biological processes such as energy metabolism, circadian rhythm, DNA repair, inflammation, cell differentiation, and organ development. The altered placental methylation of these genes was, in some studies, associated with adverse birth outcomes such as low birth weight, small for gestational age, and decreased head circumference. Moreover, few studies indicate that DNA methylation changes in the placenta were sex-specific, and infants born with altered placental DNA methylation patterns were predisposed to developing neurobehavioral abnormalities, cancer, and atopic dermatitis. These findings highlight the importance of more effective and stricter environmental and public health policies to reduce air pollution and protect human health.
Prenatal methylmercury exposure and DNA methylation in seven-year-old children in the Seychelles Child Development Study.
Andrea Cediel Ulloa, Anda Gliga, Tanzy M Love, Daniela Pineda, Daniel W Mruzek, Gene E Watson, Philip W Davidson, Conrad F Shamlaye, J J Strain, Gary J Myers, Edwin van Wijngaarden, Joelle Ruegg, Karin Broberg
Methylmercury (MeHg) is present in fish and is a neurotoxicant at sufficiently high levels. One potential mechanism of MeHg toxicity early in life is epigenetic dysregulation that may affect long-t
erm neurodevelopment. Altered DNA methylation of nervous system-related genes has been associated with adult mental health outcomes.
DNA methylation in children with prenatal methamphetamine exposure and environmental adversity.
Oluwadamilola O Oni-Orisan, Lynne M Dansereau, Carmen J Marsit, Lynne M Smith, Charles R Neal, Sheri A Della Grotta, James F Padbury, Barry M Lester
Methamphetamine (MA) use during pregnancy is a significant public health concern in the United States and affects long-term brain and behavioral development in children. We hypothesized that prenat
al MA exposure would be related to greater DNA methylation of HSD11B2 and postnatal environmental stress.
Prenatal programming of depression: cumulative risk or mismatch in the Ontario Child Health Study?
Calan Savoy, Ryan J Van Lieshout
Consistent with cumulative risk hypotheses of psychopathology, studies examining prenatal adversity and later mental health largely suggest that pre and postnatal stress exposures have summative ef
fects. Fewer data support that a mismatch in stress levels between pre- and postnatal life increases risk (the mismatch hypothesis). In this retrospective cohort study using data from the 1983 Ontario Child Health Study (OCHS), we examined interactions between birth weight status and childhood/adolescent stress to predict major depression in adulthood. Ninety-five participants born at low birth weight (LBW; <2500 g) and 972 normal birth weight (NBW) control participants completed the Composite International Diagnostic Interview Short-Form Major Depression module at 21-34 years of age. A youth risk scale consisting of five stressful exposures (family dysfunction, socioeconomic disadvantage, parental criminality, maternal mental illness, exposure to other life stresses) indexed child/adolescent adversity. Birth weight groups did not differ by childhood risk score nor depression levels. A significant interaction was observed between birth weight and the youth risk scale whereby exposure to increasing levels of exposure to childhood/adolescent adversity predicted increased levels of depression in the NBW group, but lower rates in those born at LBW. Consistent with the mismatch hypothesis, data from a large, longitudinally followed cohort suggest that the mental health of adults born LBW may be more resilient to the adverse effects of childhood/adolescent stress. Taken in the context of previous studies of low birth weight infants, these findings suggest that the nature of associations between gestational stress and later mental health may depend on the magnitude of prenatal stress exposure, as well as the degree of resilience and/or plasticity conferred by their early-life environment.
Association of Prenatal Alcohol Exposure and Prenatal Maternal Depression with Offspring Low-Grade Inflammation in Early Adolescence.
Janina Maschke, Jakob Roetner, Sophia Bösl, Anne-Christine Plank, Nicolas Rohleder, Tamme W Goecke, Peter A Fasching, Matthias W Beckmann, Oliver Kratz, Gunther H Moll, Bernd Lenz, Johannes Kornhuber, Anna Eichler, None Imac-Mind-Consortium
(1) This longitudinal study aimed to investigate the link between prenatal alcohol exposure and prenatal maternal depression with the offspring's low-grade inflammatory status. (2) Prenatal alcohol
exposure was determined via maternal self-report during the 3rd trimester of pregnancy (self-report+:
Prenatal Diet and Children's Trajectories of Anxiety and Depression Symptoms from 3 to 8 Years: The EDEN Mother-Child Cohort.
Ophélie A Collet, Barbara Heude, Anne Forhan, Cécile Delcourt, Massimiliano Orri, Judith Van der Waerden, Maria Melchior, Sylvana Côté, Sandrine Lioret, Blandine de Lauzon-Guillain, Cédric Galéra
Maternal diet quality during pregnancy has been linked to offspring's physical and mental health outcomes across the lifespan. However, few studies have examined its association with subsequent off
spring's anxiety and depression issues.
Evaluating the challenges and reproducibility of studies investigating DNA methylation signatures of psychological stress.
Yun Zhang, Chunyu Liu
Psychological stress can increase the risk of a wide range of negative health outcomes. Studies have been completed to determine if DNA methylation changes occur in the human brain because of stres
s and are associated with long-term effects and disease, but results have been inconsistent. Human candidate gene studies (150) and epigenome-wide association studies (67) were systematically evaluated to assess how DNA methylation is impacted by stress during the prenatal period, early childhood and adulthood. The association between DNA methylation of
Maternal glycaemic and insulinemic status and newborn DNA methylation: findings in women with overweight and obesity.
Marion Lecorguillé, Fionnuala M McAuliffe, Patrick J Twomey, Karien Viljoen, John Mehegan, Cecily C Kelleher, Matthew Suderman, Catherine M Phillips
Maternal dysglycaemia and pre-pregnancy obesity are associated with adverse offspring outcomes. Epigenetic mechanisms such as DNA methylation (DNAm) could contribute.
Cord blood DNA methylation modifications in infants are associated with white matter microstructure in the context of prenatal maternal depression and anxiety.
Douglas C Dean, Andy Madrid, Elizabeth M Planalp, Jason F Moody, Ligia A Papale, Karla M Knobel, Elizabeth K Wood, Ryan M McAdams, Christopher L Coe, H Hill Goldsmith, Richard J Davidson, Reid S Alisch, Pamela J Kling
Maternal and environmental factors influence brain networks and architecture via both physiological pathways and epigenetic modifications. In particular, prenatal maternal depression and anxiety sy
mptoms appear to impact infant white matter (WM) microstructure, leading us to investigate whether epigenetic modifications (i.e., DNA methylation) contribute to these WM differences. To determine if infants of women with depression and anxiety symptoms exhibit epigenetic modifications linked to neurodevelopmental changes, 52 umbilical cord bloods (CBs) were profiled. We observed 219 differentially methylated genomic positions (DMPs; FDR p < 0.05) in CB that were associated with magnetic resonance imaging measures of WM microstructure at 1 month of age and in regions previously described to be related to maternal depression and anxiety symptoms. Genomic characterization of these associated DMPs revealed 143 unique genes with significant relationships to processes involved in neurodevelopment, GTPase activity, or the canonical Wnt signaling pathway. Separate regression models for female (n = 24) and male (n = 28) infants found 142 associated DMPs in females and 116 associated DMPs in males (nominal p value < 0.001, R > 0.5), which were annotated to 98 and 81 genes, respectively. Together, these findings suggest that umbilical CB DNA methylation levels at birth are associated with 1-month WM microstructure.
Prenatal stress and offspring depression in adulthood: The mediating role of childhood trauma.
Yiwen Liu, Jon Heron, Matthew Hickman, Stanley Zammit, Dieter Wolke
There is repeated evidence for a prenatal programming effect for the development of offspring depression. However, examination of environmental influences along this pathway is sparse. This study a
imed to investigate the direct and indirect effects of pre- and postnatal stress on offspring depression in adulthood, via increased exposure to childhood trauma.
Prenatal alcohol and tobacco use and the risk of depression in offspring at age of 17 years: findings from the Raine Study.
Bereket Duko, Gavin Pereira, Kim Betts, Robert J Tait, John Newnham, Rosa Alati
Prenatal alcohol and tobacco exposures have been associated with adverse mental health consequences in offspring. The objective of this study was to test the associations between maternal prenatal
alcohol and tobacco exposures and depressive symptoms in the offspring, adjusting for a wide range of potential confounders.
DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.
Bonnie R Joubert, Janine F Felix, Paul Yousefi, Kelly M Bakulski, Allan C Just, Carrie Breton, Sarah E Reese, Christina A Markunas, Rebecca C Richmond, Cheng-Jian Xu, Leanne K Küpers, Sam S Oh, Cathrine Hoyo, Olena Gruzieva, Cilla Söderhäll, Lucas A Salas, Nour Baïz, Hongmei Zhang, Johanna Lepeule, Carlos Ruiz, Symen Ligthart, Tianyuan Wang, Jack A Taylor, Liesbeth Duijts, Gemma C Sharp, Soesma A Jankipersadsing, Roy M Nilsen, Ahmad Vaez, M Daniele Fallin, Donglei Hu, Augusto A Litonjua, Bernard F Fuemmeler, Karen Huen, Juha Kere, Inger Kull, Monica Cheng Munthe-Kaas, Ulrike Gehring, Mariona Bustamante, Marie José Saurel-Coubizolles, Bilal M Quraishi, Jie Ren, Jörg Tost, Juan R Gonzalez, Marjolein J Peters, Siri E Håberg, Zongli Xu, Joyce B van Meurs, Tom R Gaunt, Marjan Kerkhof, Eva Corpeleijn, Andrew P Feinberg, Celeste Eng, Andrea A Baccarelli, Sara E Benjamin Neelon, Asa Bradman, Simon Kebede Merid, Anna Bergström, Zdenko Herceg, Hector Hernandez-Vargas, Bert Brunekreef, Mariona Pinart, Barbara Heude, Susan Ewart, Jin Yao, Nathanaël Lemonnier, Oscar H Franco, Michael C Wu, Albert Hofman, Wendy McArdle, Pieter Van der Vlies, Fahimeh Falahi, Matthew W Gillman, Lisa F Barcellos, Ashish Kumar, Magnus Wickman, Stefano Guerra, Marie-Aline Charles, John Holloway, Charles Auffray, Henning W Tiemeier, George Davey Smith, Dirkje Postma, Marie-France Hivert, Brenda Eskenazi, Martine Vrijheid, Hasan Arshad, Josep M Antó, Abbas Dehghan, Wilfried Karmaus, Isabella Annesi-Maesano, Jordi Sunyer, Akram Ghantous, Göran Pershagen, Nina Holland, Susan K Murphy, Dawn L DeMeo, Esteban G Burchard, Christine Ladd-Acosta, Harold Snieder, Wenche Nystad, Gerard H Koppelman, Caroline L Relton, Vincent W V Jaddoe, Allen Wilcox, Erik Melén, Stephanie J London
Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health pro
blem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation.
Nadine Provençal, Janine Arloth, Annamaria Cattaneo, Christoph Anacker, Nadia Cattane, Tobias Wiechmann, Simone Röh, Maik Ködel, Torsten Klengel, Darina Czamara, Nikola S Müller, Jari Lahti, None None, Katri Räikkönen, Carmine M Pariante, Elisabeth B Binder
Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neur
ogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG dinucleotides and in the expression of 3,857 transcripts (false discovery rate [FDR] ≤ 0.1 and absolute fold change [FC] expression ≥ 1.15). HPC expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into 4 trajectories over HPC differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting expression changes but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a polyepigenetic score that predicted exposure to conditions associated with altered prenatal GCs in newborn's cord blood DNA. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.
Updates to data versions and analytic methods influence the reproducibility of results from epigenome-wide association studies.
Alexandre A Lussier, Yiwen Zhu, Brooke J Smith, Andrew J Simpkin, Andrew D A C Smith, Matthew J Suderman, Esther Walton, Kerry J Ressler, Erin C Dunn
Biomedical research has grown increasingly cooperative through the sharing of consortia-level epigenetic data. Since consortia preprocess data prior to distribution, new processing pipelines can le
ad to different versions of the same dataset. Similarly, analytic frameworks evolve to incorporate cutting-edge methods and best practices. However, it remains unknown how different data and analytic versions alter the results of epigenome-wide analyses, which could influence the replicability of epigenetic associations. Thus, we assessed the impact of these changes using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We analysed DNA methylation from two data versions, processed using separate preprocessing and analytic pipelines, examining associations between seven childhood adversities or prenatal smoking exposure and DNA methylation at age 7. We performed two sets of analyses: (1) epigenome-wide association studies (EWAS); (2) Structured Life Course Modelling Approach (SLCMA), a two-stage method that models time-dependent effects. SLCMA results were also compared across two analytic versions. Data version changes impacted both EWAS and SLCMA analyses, yielding different associations at conventional p-value thresholds. However, the magnitude and direction of associations was generally consistent between data versions, regardless of p-values. Differences were especially apparent in analyses of childhood adversity, while smoking associations were more consistent using significance thresholds. SLCMA analytic versions similarly altered top associations, but time-dependent effects remained concordant. Alterations to data and analytic versions influenced the results of epigenome-wide analyses. Our findings highlight that magnitude and direction are better measures for replication and stability than p-value thresholds.
Maternal attachment insecurity, maltreatment history, and depressive symptoms are associated with broad DNA methylation signatures in infants.
Thalia K Robakis, Marissa C Roth, Lucy S King, Kathryn L Humphreys, Marcus Ho, Xianglong Zhang, Yuhao Chen, Tongbin Li, Natalie L Rasgon, Kathleen T Watson, Alexander E Urban, Ian H Gotlib
The early environment, including maternal characteristics, provides many cues to young organisms that shape their long-term physical and mental health. Identifying the earliest molecular events tha
t precede observable developmental outcomes could help identify children in need of support prior to the onset of physical and mental health difficulties. In this study, we examined whether mothers' attachment insecurity, maltreatment history, and depressive symptoms were associated with alterations in DNA methylation patterns in their infants, and whether these correlates in the infant epigenome were associated with socioemotional and behavioral functioning in toddlerhood. We recruited 156 women oversampled for histories of depression, who completed psychiatric interviews and depression screening during pregnancy, then provided follow-up behavioral data on their children at 18 months. Buccal cell DNA was obtained from 32 of their infants for a large-scale analysis of methylation patterns across 5 × 10
Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models.
Benjamin I Laufer, Yu Hasegawa, Zhichao Zhang, Casey E Hogrefe, Laura A Del Rosso, Lori Haapanen, Hyeyeon Hwang, Melissa D Bauman, Judy Van de Water, Ameer Y Taha, Carolyn M Slupsky, Mari S Golub, John P Capitanio, Catherine A VandeVoort, Cheryl K Walker, Janine M LaSalle
Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in
rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain. The DMRs were enriched for neurodevelopmental functions, methylation-sensitive developmental transcription factor motifs, and human NDD DMRs identified from brain and placenta. Brain and cffDNA methylation levels from a large region overlapping mir-663 correlated with maternal obesity, metabolic and immune markers, and infant behavior. A DUX4 hippocampal co-methylation network correlated with maternal obesity, infant behavior, infant hippocampal lipidomic and metabolomic profiles, and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and metabolites. We conclude that in this model, maternal obesity was associated with changes in the infant brain and behavior, and these differences were detectable in pregnancy through integrative analyses of cffDNA methylation with immune and metabolic factors.