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

Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium

Research output: Contribution to journalArticle

602 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)497-511
Number of pages15
JournalMolecular Psychiatry
Volume18
Issue number4
DOIs
Publication statusPublished - 2013 Apr 1

Fingerprint

Genome-Wide Association Study
Major Depressive Disorder
Single Nucleotide Polymorphism
Bipolar Disorder
Genome
Genetic Research

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (2013). A mega-Analysis of genome-wide association studies for major depressive disorder. Molecular Psychiatry, 18(4), 497-511. https://doi.org/10.1038/mp.2012.21
Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium. / A mega-Analysis of genome-wide association studies for major depressive disorder. In: Molecular Psychiatry. 2013 ; Vol. 18, No. 4. pp. 497-511.
@article{65cda0f177924d78833c9228bc8cf7e8,
title = "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.",
author = "{Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium} and Sullivan, {Patrick F.} and Daly, {Mark J.} and Stephan Ripke and Lewis, {Cathryn M.} and Lin, {Dan Yu} and Wray, {Naomi R.} and Benjamin Neale and Levinson, {Douglas F.} and Gerome Breen and Byrne, {Enda M.} and Marcella Rietschel and Witte Hoogendijk and Hamilton, {Steven P.} and Weissman, {Myrna M.} and Ren{\'e} Breuer and Sven Cichon and Franziska Degenhardt and Josef Frank and Magdalena Gross and Stefan Herms and Susanne Hoefels and Wolfgang Maier and Manuel Mattheisen and N{\"o}ethen, {Markus M.} and Schulze, {Thomas G.} and Michael Steffens and Jens Treutlein and Boomsma, {Dorret I.} and {De Geus}, {Eco J.} and {Jan Hottenga}, Jouke and Tzeng Jung-Ying and Jung-Ying Tzeng and Nolen, {Willem A.} and Penninx, {Brenda P.} and Smit, {Johannes H.} and {van Grootheest}, Gerard and Gonneke Willemsen and Zitman, {Frans G.} and Coryell, {William H.} and Knowles, {James A.} and Lawson, {William B.} and Potash, {James B.} and Scheftner, {William A.} and Jianxin Shi and Florian Holsboer and Pierandrea Muglia and Federica Tozzi and Blackwood, {Douglas H.R.} and MacIntyre, {Donald J.} and Andrew McIntosh",
year = "2013",
month = "4",
day = "1",
doi = "10.1038/mp.2012.21",
language = "English",
volume = "18",
pages = "497--511",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "4",

}

Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium 2013, 'A mega-Analysis of genome-wide association studies for major depressive disorder', Molecular Psychiatry, vol. 18, no. 4, pp. 497-511. https://doi.org/10.1038/mp.2012.21

A mega-Analysis of genome-wide association studies for major depressive disorder. / Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium.

In: Molecular Psychiatry, Vol. 18, No. 4, 01.04.2013, p. 497-511.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A mega-Analysis of genome-wide association studies for major depressive disorder

AU - Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium

AU - Sullivan, Patrick F.

AU - Daly, Mark J.

AU - Ripke, Stephan

AU - Lewis, Cathryn M.

AU - Lin, Dan Yu

AU - Wray, Naomi R.

AU - Neale, Benjamin

AU - Levinson, Douglas F.

AU - Breen, Gerome

AU - Byrne, Enda M.

AU - Rietschel, Marcella

AU - Hoogendijk, Witte

AU - Hamilton, Steven P.

AU - Weissman, Myrna M.

AU - Breuer, René

AU - Cichon, Sven

AU - Degenhardt, Franziska

AU - Frank, Josef

AU - Gross, Magdalena

AU - Herms, Stefan

AU - Hoefels, Susanne

AU - Maier, Wolfgang

AU - Mattheisen, Manuel

AU - Nöethen, Markus M.

AU - Schulze, Thomas G.

AU - Steffens, Michael

AU - Treutlein, Jens

AU - Boomsma, Dorret I.

AU - De Geus, Eco J.

AU - Jan Hottenga, Jouke

AU - Jung-Ying, Tzeng

AU - Tzeng, Jung-Ying

AU - Nolen, Willem A.

AU - Penninx, Brenda P.

AU - Smit, Johannes H.

AU - van Grootheest, Gerard

AU - Willemsen, Gonneke

AU - Zitman, Frans G.

AU - Coryell, William H.

AU - Knowles, James A.

AU - Lawson, William B.

AU - Potash, James B.

AU - Scheftner, William A.

AU - Shi, Jianxin

AU - Holsboer, Florian

AU - Muglia, Pierandrea

AU - Tozzi, Federica

AU - Blackwood, Douglas H.R.

AU - MacIntyre, Donald J.

AU - McIntosh, Andrew

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84879892380&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879892380&partnerID=8YFLogxK

U2 - 10.1038/mp.2012.21

DO - 10.1038/mp.2012.21

M3 - Article

C2 - 22472876

AN - SCOPUS:84879892380

VL - 18

SP - 497

EP - 511

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 4

ER -

Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium. A mega-Analysis of genome-wide association studies for major depressive disorder. Molecular Psychiatry. 2013 Apr 1;18(4):497-511. https://doi.org/10.1038/mp.2012.21