Dataset Information

A mega-analysis of genome-wide association studies for major depressive disorder.

ABSTRACT: Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18?759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50?695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248?kb interval of high LD on 3p21.1 (chr3:52?425?083-53?822?102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

SUBMITTER: Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium

PROVIDER: S-EPMC3837431 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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A mega-analysis of genome-wide association studies for major depressive disorder.

Ripke Stephan S Wray Naomi R NR Lewis Cathryn M CM Hamilton Steven P SP Weissman Myrna M MM Breen Gerome G Byrne Enda M EM Blackwood Douglas H R DH Boomsma Dorret I DI Cichon Sven S Heath Andrew C AC Holsboer Florian F Lucae Susanne S Madden Pamela A F PA Martin Nicholas G NG McGuffin Peter P Muglia Pierandrea P Noethen Markus M MM Penninx Brenda P BP Pergadia Michele L ML Potash James B JB Rietschel Marcella M Lin Danyu D Müller-Myhsok Bertram B Shi Jianxin J Steinberg Stacy S Grabe Hans J HJ Lichtenstein Paul P Magnusson Patrik P Perlis Roy H RH Preisig Martin M Smoller Jordan W JW Stefansson Kari K Uher Rudolf R Kutalik Zoltan Z Tansey Katherine E KE Teumer Alexander A Viktorin Alexander A Barnes Michael R MR Bettecken Thomas T Binder Elisabeth B EB Breuer René R Castro Victor M VM Churchill Susanne E SE Coryell William H WH Craddock Nick N Craig Ian W IW Czamara Darina D De Geus Eco J EJ Degenhardt Franziska F Farmer Anne E AE Fava Maurizio M Frank Josef J Gainer Vivian S VS Gallagher Patience J PJ Gordon Scott D SD Goryachev Sergey S Gross Magdalena M Guipponi Michel M Henders Anjali K AK Herms Stefan S Hickie Ian B IB Hoefels Susanne S Hoogendijk Witte W Hottenga Jouke Jan JJ Iosifescu Dan V DV Ising Marcus M Jones Ian I Jones Lisa L Jung-Ying Tzeng T Knowles James A JA Kohane Isaac S IS Kohli Martin A MA Korszun Ania A Landen Mikael M Lawson William B WB Lewis Glyn G Macintyre Donald D Maier Wolfgang W Mattheisen Manuel M McGrath Patrick J PJ McIntosh Andrew A McLean Alan A Middeldorp Christel M CM Middleton Lefkos L Montgomery Grant M GM Murphy Shawn N SN Nauck Matthias M Nolen Willem A WA Nyholt Dale R DR O'Donovan Michael M Oskarsson Högni H Pedersen Nancy N Scheftner William A WA Schulz Andrea A Schulze Thomas G TG Shyn Stanley I SI Sigurdsson Engilbert E Slager Susan L SL Smit Johannes H JH Stefansson Hreinn H Steffens Michael M Thorgeirsson Thorgeir T Tozzi Federica F Treutlein Jens J Uhr Manfred M van den Oord Edwin J C G EJ Van Grootheest Gerard G Völzke Henry H Weilburg Jeffrey B JB Willemsen Gonneke G Zitman Frans G FG Neale Benjamin B Daly Mark M Levinson Douglas F DF Sullivan Patrick F PF

Molecular psychiatry 20120403 4

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 55 ...[more]

PMID: 22472876

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Project description:IMPORTANCE:Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases). OBJECTIVES:To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. DESIGN, SETTING, AND PARTICIPANTS:Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. MAIN OUTCOMES AND MEASURES:Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. RESULTS:A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P?=?9.26?×?10-9 in the discovery meta-analysis). This association was not replicated (P?=?.32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P?=?2.38?×?10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09?×?10-12?<?P?<?.05) and MDD (4.02?×?10-9?<?P?<?.05) in the 2 other cohorts. CONCLUSIONS AND RELEVANCE:This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.

Dataset Information

A mega-analysis of genome-wide association studies for major depressive disorder.

Publications

A mega-analysis of genome-wide association studies for major depressive disorder.

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