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.
authors.affiliation: Harvard University/Broad Institute, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Steven P
authors.initials: SP
authors.lastname: Hamilton
authors.forename: Myrna M
authors.initials: MM
authors.lastname: Weissman
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.forename: Enda M
authors.initials: EM
authors.lastname: Byrne
authors.forename: Douglas H R
authors.initials: DH
authors.lastname: Blackwood
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Pierandrea
authors.initials: P
authors.lastname: Muglia
authors.forename: Markus M
authors.initials: MM
authors.lastname: Noethen
authors.forename: Brenda P
authors.initials: BP
authors.lastname: Penninx
authors.forename: Michele L
authors.initials: ML
authors.lastname: Pergadia
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Danyu
authors.initials: D
authors.lastname: Lin
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.forename: Stacy
authors.initials: S
authors.lastname: Steinberg
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Grabe
authors.forename: Paul
authors.initials: P
authors.lastname: Lichtenstein
authors.forename: Patrik
authors.initials: P
authors.lastname: Magnusson
authors.forename: Roy H
authors.initials: RH
authors.lastname: Perlis
authors.forename: Martin
authors.initials: M
authors.lastname: Preisig
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Smoller
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Kutalik
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Tansey
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Alexander
authors.initials: A
authors.lastname: Viktorin
authors.forename: Michael R
authors.initials: MR
authors.lastname: Barnes
authors.forename: Thomas
authors.initials: T
authors.lastname: Bettecken
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.forename: René
authors.initials: R
authors.lastname: Breuer
authors.forename: Victor M
authors.initials: VM
authors.lastname: Castro
authors.forename: Susanne E
authors.initials: SE
authors.lastname: Churchill
authors.forename: William H
authors.initials: WH
authors.lastname: Coryell
authors.forename: Nick
authors.initials: N
authors.lastname: Craddock
authors.forename: Ian W
authors.initials: IW
authors.lastname: Craig
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.forename: Eco J
authors.initials: EJ
authors.lastname: De Geus
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.forename: Anne E
authors.initials: AE
authors.lastname: Farmer
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fava
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.forename: Vivian S
authors.initials: VS
authors.lastname: Gainer
authors.forename: Patience J
authors.initials: PJ
authors.lastname: Gallagher
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gordon
authors.forename: Sergey
authors.initials: S
authors.lastname: Goryachev
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gross
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.forename: Ian B
authors.initials: IB
authors.lastname: Hickie
authors.forename: Susanne
authors.initials: S
authors.lastname: Hoefels
authors.forename: Witte
authors.initials: W
authors.lastname: Hoogendijk
authors.forename: Jouke Jan
authors.initials: JJ
authors.lastname: Hottenga
authors.forename: Dan V
authors.initials: DV
authors.lastname: Iosifescu
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.forename: Ian
authors.initials: I
authors.lastname: Jones
authors.forename: Lisa
authors.initials: L
authors.lastname: Jones
authors.forename: Tzeng
authors.initials: T
authors.lastname: Jung-Ying
authors.forename: James A
authors.initials: JA
authors.lastname: Knowles
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kohli
authors.forename: Ania
authors.initials: A
authors.lastname: Korszun
authors.forename: Mikael
authors.initials: M
authors.lastname: Landen
authors.forename: William B
authors.initials: WB
authors.lastname: Lawson
authors.forename: Glyn
authors.initials: G
authors.lastname: Lewis
authors.forename: Donald
authors.initials: D
authors.lastname: Macintyre
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McGrath
authors.forename: Andrew
authors.initials: A
authors.lastname: McIntosh
authors.forename: Alan
authors.initials: A
authors.lastname: McLean
authors.forename: Christel M
authors.initials: CM
authors.lastname: Middeldorp
authors.forename: Lefkos
authors.initials: L
authors.lastname: Middleton
authors.forename: Grant M
authors.initials: GM
authors.lastname: Montgomery
authors.forename: Shawn N
authors.initials: SN
authors.lastname: Murphy
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.forename: Willem A
authors.initials: WA
authors.lastname: Nolen
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Högni
authors.initials: H
authors.lastname: Oskarsson
authors.forename: Nancy
authors.initials: N
authors.lastname: Pedersen
authors.forename: William A
authors.initials: WA
authors.lastname: Scheftner
authors.forename: Andrea
authors.initials: A
authors.lastname: Schulz
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Shyn
authors.forename: Engilbert
authors.initials: E
authors.lastname: Sigurdsson
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Smit
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.forename: Thorgeir
authors.initials: T
authors.lastname: Thorgeirsson
authors.forename: Federica
authors.initials: F
authors.lastname: Tozzi
authors.forename: Jens
authors.initials: J
authors.lastname: Treutlein
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Edwin J C G
authors.initials: EJ
authors.lastname: van den Oord
authors.forename: Gerard
authors.initials: G
authors.lastname: Van Grootheest
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Weilburg
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Frans G
authors.initials: FG
authors.lastname: Zitman
authors.forename: Benjamin
authors.initials: B
authors.lastname: Neale
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Levinson
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics