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

重性抑郁障碍 全基因组关联研究 单核苷酸多态性 遗传关联 双相情感障碍 肿瘤科 遗传学 医学 内科学 生物 基因型 基因 锂(药物) 扁桃形结构
作者
Stephan Ripke,Naomi R. Wray,Cathryn M. Lewis,Steven P. Hamilton,Myrna M. Weissman,Gerome Breen,Enda M. Byrne,Douglas Blackwood,Dorret I. Boomsma,Sven Cichon,Andrew C. Heath,Herta Flor,Susanne Lucae,Pamela A. F. Madden,Nicholas G. Martin,Peter McGuffin,Pierandrea Muglia,Markus M. Nöethen,Brenda P Penninx,Michele L. Pergadia,James B. Potash,Marcella Rietschel,D. Y. Lin,Bertram Müller‐Myhsok,Jianxin Shi,Stacy Steinberg,Hans J. Grabe,Paul Lichtenstein,Patrik K. E. Magnusson,Roy H. Perlis,Martin Preisig,Jordan W. Smoller,Kāri Stefánsson,Rudolf Uher,Zoltán Kutalik,Katherine E. Tansey,Alexander Teumer,Alexander Viktorin,Michael R. Barnes,Thomas Bettecken,Elisabeth B. Binder,René Breuer,Víctor M. Castro,Susanne Churchill,William Coryell,Nick Craddock,Ian Craig,Darina Czamara,Eco J. C. de Geus,Franziska Degenhardt,Anne Farmer,Maurizio Fava,Josef Frank,Vivian S. Gainer,Patience Gallagher,Scott D. Gordon,Sergey Goryachev,Magdalena Groß,Michel Guipponi,Anjali K. Henders,Stefan Herms,Ian B. Hickie,Susanne Hoefels,Witte J.G. Hoogendijk,Jouke‐Jan Hottenga,Dan V. Iosifescu,Marcus Ising,Ian D. Jones,Lisa Jones,Tzeng Jung-Ying,James A. Knowles,Isaac S. Kohane,Martin Kohli,Ania Korszun,Mikael Landén,William Lawson,Glyn Lewis,Donald J. MacIntyre,Wolfgang Maier,Manuel Mattheisen,Patrick J. McGrath,Andrew M. McIntosh,Alan McLean,Christel M. Middeldorp,Lefkos Middleton,Grant Montgomery,Shawn N. Murphy,Matthias Nauck,Willem A. Nolen,Dale R. Nyholt,Michael O’Donovan,Högni Óskarsson,Nancy L. Pedersen,William A. Scheftner,Andrea Schulz,Thomas G. Schulze,Stanley I. Shyn,Engilbert Sigurðsson,Susan L. Slager,Johannes H. Smit,Hreinn Stefánsson,Michael Steffens,Thorgeir E. Thorgeirsson,Federica Tozzi,Jens Treutlein,Manfred Uhr,Edwin J.C.G. van den Oord,Gerard van Grootheest,Henry Völzke,Jeffrey B. Weilburg,Gonneke Willemsen,Frans G. Zitman,Benjamin M. Neale,Mark J. Daly,Douglas F. Levinson,Patrick F. Sullivan
出处
期刊:Molecular Psychiatry [Springer Nature]
卷期号:18 (4): 497-511 被引量:1093
标识
DOI:10.1038/mp.2012.21
摘要

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.
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