An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.

Nese Direk Stephanie Williams Jennifer A Smith Stephan Ripke Tracy Air Azmeraw T Amare Najaf Amin Bernhard T Baune David A Bennett Douglas H R Blackwood Dorret Boomsma Gerome Breen Henriette N Buttenschøn Enda M Byrne Anders D Børglum Enrique Castelao Sven Cichon Toni-Kim Clarke Marilyn C Cornelis Udo Dannlowski Philip L De Jager Ayse Demirkan Enrico Domenici Cornelia M van Duijn Erin C Dunn Johan G Eriksson Tonu Esko Jessica D Faul Luigi Ferrucci Myriam Fornage Eco de Geus Michael Gill Scott D Gordon Hans Jörgen Grabe Gerard van Grootheest Steven P Hamilton Catharina A Hartman Andrew C Heath Karin Hek Albert Hofman Georg Homuth Carsten Horn Jouke Jan Hottenga Sharon L R Kardia Stefan Kloiber Karestan Koenen Zoltán Kutalik Karl-Heinz Ladwig Jari Lahti Douglas F Levinson Cathryn M Lewis Glyn Lewis Qingqin S Li David J Llewellyn Susanne Lucae Kathryn L Lunetta Donald J MacIntyre Pamela Madden Nicholas G Martin Andrew M McIntosh Andres Metspalu Yuri Milaneschi Grant W Montgomery Ole Mors Thomas H Mosley Joanne M Murabito Bertram Müller-Myhsok Markus M Nöthen Dale R Nyholt Michael C O'Donovan Brenda W Penninx Michele L Pergadia Roy Perlis James B Potash Martin Preisig Shaun M Purcell Jorge A Quiroz Katri Räikkönen John P Rice Marcella Rietschel Margarita Rivera Thomas G Schulze Jianxin Shi Stanley Shyn Grant C Sinnamon Johannes H Smit Jordan W Smoller Harold Snieder Toshiko Tanaka Katherine E Tansey Alexander Teumer Rudolf Uher Daniel Umbricht Sandra Van der Auwera Erin B Ware David R Weir Myrna M Weissman Gonneke Willemsen Jingyun Yang Wei Zhao Henning Tiemeier Patrick F Sullivan

Biol Psychiatry 2017 09 8;82(5):322-329. Epub 2016 Dec 8.

Department of Psychiatry, Genomic Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Center for Psychiatric Genomics, Genomic Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.

Background: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.

Methods: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.

Results: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10).

Conclusions: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

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