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

Artikel i vetenskaplig tidskrift
Författare Stephan Ripke
Naomi R Wray
Cathryn M Lewis
Steven P Hamilton
Myrna M Weissman
Gerome Breen
Enda M Byrne
Douglas H R Blackwood
Dorret I Boomsma
Sven Cichon
Andrew C Heath
Florian Holsboer
Susanne Lucae
Pamela A F Madden
Nicholas G Martin
Peter McGuffin
Pierandrea Muglia
Markus M Noethen
Brenda P Penninx
Michele L Pergadia
James B Potash
Marcella Rietschel
Danyu Lin
Bertram Müller-Myhsok
Jianxin Shi
Stacy Steinberg
Hans J Grabe
Paul Lichtenstein
Patrik Magnusson
Roy H Perlis
Martin Preisig
Jordan W Smoller
Kari Stefansson
Rudolf Uher
Zoltan Kutalik
Katherine E Tansey
Alexander Teumer
Alexander Viktorin
Michael R Barnes
Thomas Bettecken
Elisabeth B Binder
René Breuer
Victor M Castro
Susanne E Churchill
William H Coryell
Nick Craddock
Ian W Craig
Darina Czamara
Eco J De Geus
Franziska Degenhardt
Anne E Farmer
Maurizio Fava
Josef Frank
Vivian S Gainer
Patience J Gallagher
Scott D Gordon
Sergey Goryachev
Magdalena Gross
Michel Guipponi
Anjali K Henders
Stefan Herms
Ian B Hickie
Susanne Hoefels
Witte Hoogendijk
Jouke Jan Hottenga
Dan V Iosifescu
Marcus Ising
Ian Jones
Lisa Jones
Tzeng Jung-Ying
James A Knowles
Isaac S Kohane
Martin A Kohli
Ania Korszun
Mikael Landén
William B Lawson
Glyn Lewis
Donald Macintyre
Wolfgang Maier
Manuel Mattheisen
Patrick J McGrath
Andrew McIntosh
Alan McLean
Christel M Middeldorp
Lefkos Middleton
Grant M Montgomery
Shawn N Murphy
Matthias Nauck
Willem A Nolen
Dale R Nyholt
Michael O'Donovan
Högni Oskarsson
Nancy Pedersen
William A Scheftner
Andrea Schulz
Thomas G Schulze
Stanley I Shyn
Engilbert Sigurdsson
Susan L Slager
Johannes H Smit
Hreinn Stefansson
Michael Steffens
Thorgeir 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 Neale
Mark Daly
Douglas F Levinson
Patrick F Sullivan
Publicerad i Molecular psychiatry
Volym 18
Nummer/häfte 4
Sidor 497-511
ISSN 1476-5578
Publiceringsår 2013
Publicerad vid Institutionen för neurovetenskap och fysiologi
Sidor 497-511
Språk en
Länkar dx.doi.org/10.1038/mp.2012.21
Ämnesord genetics; genome-wide association study; major depressive disorder; mega-analysis; meta-analysis
Ämneskategorier Psykiatri

Sammanfattning

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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