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

被引：801

作者：

Sullivan, Patrick F. ^{[1
,15
]}

Daly, Mark J. ^{[2
]}

Ripke, Stephan ^{[2
]}

Lewis, Cathryn M. ^{[4
]}

Lin, Dan-Yu ^{[15
]}

Wray, Naomi R. ^{[3
]}

Neale, Benjamin

Levinson, Douglas F. ^{[35
]}

Breen, Gerome ^{[4
]}

Byrne, Enda M. ^{[11
]}

Wray, Naomi R. ^{[3
]}

Levinson, Douglas F. ^{[35
]}

Rietschel, Marcella ^{[14
]}

Hoogendijk, Witte

Ripke, Stephan ^{[2
]}

Sullivan, Patrick F. ^{[1
,15
]}

Hamilton, Steven P. ^{[5
]}

Levinson, Douglas F. ^{[35
]}

Lewis, Cathryn M. ^{[4
]}

Ripke, Stephan ^{[2
]}

Weissman, Myrna M. ^{[6
]}

Wray, Naomi R. ^{[3
]}

Breuer, Rene ^{[14
]}

Cichon, Sven ^{[9
]}

Degenhardt, Franziska ^{[9
]}

Frank, Josef ^{[14
]}

Gross, Magdalena ^{[9
]}

Herms, Stefan ^{[9
]}

Hoefels, Susanne ^{[9
]}

Maier, Wolfgang ^{[9
]}

Mattheisen, Manuel ^{[9
]}

Noeethen, Markus M. ^{[9
]}

Rietschel, Marcella ^{[14
]}

Schulze, Thomas G.

Steffens, Michael ^{[9
]}

Treutlein, Jens ^{[14
]}

Boomsma, Dorret I. ^{[8
]}

De Geus, Eco J. ^{[8
]}

Hoogendijk, Witte

Hottenga, Jouke Jan ^{[8
]}

Jung-Ying, Tzeng ^{[24
]}

Lin, Dan-Yu ^{[15
]}

Middeldorp, Christel M. ^{[8
]}

Nolen, Willem A. ^{[29
]}

Penninx, Brenda P. ^{[12
]}

Smit, Johannes H. ^{[12
]}

Sullivan, Patrick F. ^{[1
,15
]}

van Grootheest, Gerard ^{[12
]}

Willemsen, Gonneke ^{[8
]}

Zitman, Frans G. ^{[34
]}

机构：

[1] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[2] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA

[3] Univ Queensland, Queensland Inst Med Res, Brisbane, Qld 4072, Australia

[4] Kings Coll London, Inst Psychiat, London, England

[5] Univ Calif San Francisco, San Francisco, CA 94143 USA

[6] Columbia Univ, New York, NY 10027 USA

[7] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland

[8] Vrije Univ Amsterdam, Amsterdam, Netherlands

[9] Univ Bonn, Bonn, Germany

[10] Washington Univ, St Louis, MO USA

[11] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[12] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands

[13] Univ Iowa, Iowa City, IA 52242 USA

[14] Heidelberg Univ, Cent Inst Mental Hlth, Heidelberg, Germany

[15] Univ N Carolina, Chapel Hill, NC 27515 USA

[16] NCI, Bethesda, MD 20892 USA

[17] Univ Greifswald, Greifswald, Germany

[18] Karolinska Inst, S-10401 Stockholm, Sweden

[19] Massachusetts Gen Hosp, Boston, MA 02114 USA

[20] Univ Lausanne, CH-1015 Lausanne, Switzerland

[21] Cardiff Univ, Cardiff CF10 3AX, S Glam, Wales

[22] Univ Geneva, CH-1211 Geneva 4, Switzerland

[23] Univ Sydney, Sydney, NSW 2006, Australia

[24] N Carolina State Univ, Raleigh, NC 27695 USA

[25] Univ So Calif, Los Angeles, CA 90089 USA

[26] Brigham & Womens Hosp, Boston, MA 02115 USA

[27] Howard Univ, Washington, DC USA

[28] Univ Bristol, Bristol BS8 1TH, Avon, England

[29] Univ Groningen, Univ Med Ctr Groningen, NL-9700 AB Groningen, Netherlands

[30] Rush Univ, Med Ctr, Chicago, IL USA

[31] Univ Washington, Seattle, WA 98195 USA

[32] Mayo Clin, Rochester, MN 55905 USA

[33] Virginia Commonwealth Univ, Richmond, VA 23284 USA

[34] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands

[35] Stanford Univ, Stanford, CA 94305 USA

来源：

MOLECULAR PSYCHIATRY | 2013年 / 18卷 / 04期

基金：

美国国家卫生研究院; 英国医学研究理事会; 澳大利亚研究理事会; 瑞士国家科学基金会; 瑞典研究理事会; 英国惠康基金;

关键词：

genetics; genome-wide association study; major depressive disorder; mega-analysis; meta-analysis; SEROTONIN TRANSPORTER GENE; SUSCEPTIBILITY LOCI; MENTAL-DISORDERS; BIPOLAR DISORDER; MOOD DISORDERS; RISK-FACTORS; LIFE STRESS; METAANALYSIS; EPIDEMIOLOGY; TWIN;

D O I：

10.1038/mp.2012.21

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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<5x10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9x10(-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. Molecular Psychiatry (2013) 18, 497-511; doi:10.1038/mp.2012.21; published online 3 April 2012

引用

页码：497 / 511

页数：15

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