Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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A mega-analysis of genome-wide association studies for major depressive disorder.
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.
2013 Apr
aheadofprint 2012/04/03
entrez 2012/04/05 06:00
pubmed 2012/04/05 06:00
medline 2014/04/22 06:00
Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium Harvard University/Broad Institute, USA.
Ripke S Ripke Stephan S
Wray NR Wray Naomi R NR
Lewis CM Lewis Cathryn M CM
Hamilton SP Hamilton Steven P SP
Weissman MM Weissman Myrna M MM
Breen G Breen Gerome G
Byrne EM Byrne Enda M EM
Blackwood DH Blackwood Douglas H R DH
Boomsma DI Boomsma Dorret I DI
Cichon S Cichon Sven S
Heath AC Heath Andrew C AC
Holsboer F Holsboer Florian F
Lucae S Lucae Susanne S
Madden PA Madden Pamela A F PA
Martin NG Martin Nicholas G NG
McGuffin P McGuffin Peter P
Muglia P Muglia Pierandrea P
Noethen MM Noethen Markus M MM
Penninx BP Penninx Brenda P BP
Pergadia ML Pergadia Michele L ML
Potash JB Potash James B JB
Rietschel M Rietschel Marcella M
Lin D Lin Danyu D
Müller-Myhsok B Müller-Myhsok Bertram B
Shi J Shi Jianxin J
Steinberg S Steinberg Stacy S
Grabe HJ Grabe Hans J HJ
Lichtenstein P Lichtenstein Paul P
Magnusson P Magnusson Patrik P
Perlis RH Perlis Roy H RH
Preisig M Preisig Martin M
Smoller JW Smoller Jordan W JW
Stefansson K Stefansson Kari K
Uher R Uher Rudolf R
Kutalik Z Kutalik Zoltan Z
Tansey KE Tansey Katherine E KE
Teumer A Teumer Alexander A
Viktorin A Viktorin Alexander A
Barnes MR Barnes Michael R MR
Bettecken T Bettecken Thomas T
Binder EB Binder Elisabeth B EB
Breuer R Breuer René R
Castro VM Castro Victor M VM
Churchill SE Churchill Susanne E SE
Coryell WH Coryell William H WH
Craddock N Craddock Nick N
Craig IW Craig Ian W IW
Czamara D Czamara Darina D
De Geus EJ De Geus Eco J EJ
Degenhardt F Degenhardt Franziska F
Farmer AE Farmer Anne E AE
Fava M Fava Maurizio M
Frank J Frank Josef J
Gainer VS Gainer Vivian S VS
Gallagher PJ Gallagher Patience J PJ
Gordon SD Gordon Scott D SD
Goryachev S Goryachev Sergey S
Gross M Gross Magdalena M
Guipponi M Guipponi Michel M
Henders AK Henders Anjali K AK
Herms S Herms Stefan S
Hickie IB Hickie Ian B IB
Hoefels S Hoefels Susanne S
Hoogendijk W Hoogendijk Witte W
Hottenga JJ Hottenga Jouke Jan JJ
Iosifescu DV Iosifescu Dan V DV
Ising M Ising Marcus M
Jones I Jones Ian I
Jones L Jones Lisa L
Jung-Ying T Jung-Ying Tzeng T
Knowles JA Knowles James A JA
Kohane IS Kohane Isaac S IS
Kohli MA Kohli Martin A MA
Korszun A Korszun Ania A
Landen M Landen Mikael M
Lawson WB Lawson William B WB
Lewis G Lewis Glyn G
Macintyre D Macintyre Donald D
Maier W Maier Wolfgang W
Mattheisen M Mattheisen Manuel M
McGrath PJ McGrath Patrick J PJ
McIntosh A McIntosh Andrew A
McLean A McLean Alan A
Middeldorp CM Middeldorp Christel M CM
Middleton L Middleton Lefkos L
Montgomery GM Montgomery Grant M GM
Murphy SN Murphy Shawn N SN
Nauck M Nauck Matthias M
Nolen WA Nolen Willem A WA
Nyholt DR Nyholt Dale R DR
O'Donovan M O'Donovan Michael M
Oskarsson H Oskarsson Högni H
Pedersen N Pedersen Nancy N
Scheftner WA Scheftner William A WA
Schulz A Schulz Andrea A
Schulze TG Schulze Thomas G TG
Shyn SI Shyn Stanley I SI
Sigurdsson E Sigurdsson Engilbert E
Slager SL Slager Susan L SL
Smit JH Smit Johannes H JH
Stefansson H Stefansson Hreinn H
Steffens M Steffens Michael M
Thorgeirsson T Thorgeirsson Thorgeir T
Tozzi F Tozzi Federica F
Treutlein J Treutlein Jens J
Uhr M Uhr Manfred M
van den Oord EJ van den Oord Edwin J C G EJ
Van Grootheest G Van Grootheest Gerard G
Völzke H Völzke Henry H
Weilburg JB Weilburg Jeffrey B JB
Willemsen G Willemsen Gonneke G
Zitman FG Zitman Frans G FG
Neale B Neale Benjamin B
Daly M Daly Mark M
Levinson DF Levinson Douglas F DF
Sullivan PF Sullivan Patrick F PF
TITLE: Molecular psychiatry
YEAR: 2013
ISSN: 1476-5578
ISSNTYPE: Electronic
MEDLINETA: Mol Psychiatry
COUNTRY: England
ISSNLINKING: 1359-4184
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
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Bipolar Disorder genetics
Case-Control Studies genetics
Depressive Disorder, Major genetics
European Continental Ancestry Group genetics
Female genetics
Genetic Predisposition to Disease genetics
Genome-Wide Association Study statistics & numerical data
Humans statistics & numerical data
Male statistics & numerical data
Polymorphism, Single Nucleotide genetics
PMC3837431 NLM