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

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

doi:10.1016/j.biopsych.2016.11.013

Journal Article

FZJ-2017-00322

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

Direk, N. ; Williams, S. ; Smith, J. A. ; Ripke, S. ; Air, T. ; Amare, A. T. ; Amin, N. ; Baune, B. T. ; Bennett, D. A. ; Blackwood, D. H. R. ; Boomsma, D. ; Breen, G. ; Buttenschøn, H. N. ; Byrne, E. M. ; Børglum, A. D. ; Castelao, E. ; Cichon, S.FZJ* ; Clarke, T.-K. ; Cornelis, M. C. ; Dannlowski, U. ; De Jager, P. L. ; Demirkan, A. ; Domenici, E. ; van Duijn, C. M. ; Dunn, E. C. ; Eriksson, J. G. ; Esko, T. ; Faul, J. D. ; Ferrucci, L. ; Fornage, M. ; de Geus, E. ; Gill, M. ; Gordon, S. D. ; Grabe, H. J. ; van Grootheest, G. ; Hamilton, S. P. ; Hartman, C. A. ; Heath, A. C. ; Hek, K. ; Hofman, A. ; Homuth, G. ; Horn, C. ; Jan Hottenga, J. ; Kardia, S. L. R. ; Kloiber, S. ; Koenen, K. ; Kutalik, Z. ; Ladwig, K.-H. ; Lahti, J. ; Levinson, D. F. ; Lewis, C. M. ; Lewis, G. ; Li, Q. S. ; Llewellyn, D. J. ; Lucae, S. ; Lunetta, K. L. ; MacIntyre, D. J. ; Madden, P. ; Martin, N. G. ; McIntosh, A. M. ; Metspalu, A. ; Milaneschi, Y. ; Montgomery, G. W. ; Mors, O. ; Mosley, T. H. ; Murabito, J. M. ; Müller-Myhsok, B. ; Nöthen, M. M. ; Nyholt, D. R. ; O’Donovan, M. C. ; Penninx, B. W. ; Pergadia, M. L. ; Perlis, R. ; Potash, J. B. ; Preisig, M. ; Purcell, S. M. ; Quiroz, J. A. ; Räikkönen, K. ; Rice, J. P. ; Rietschel, M. ; Rivera, M. ; Schulze, T. G. ; Shi, J. ; Shyn, S. ; Sinnamon, G. C. ; Smit, J. H. ; Smoller, J. W. ; Snieder, H. ; Tanaka, T. ; Tansey, K. E. ; Teumer, A. ; Uher, R. ; Umbricht, D. ; Van der Auwera, S. ; Ware, E. B. ; Weir, D. R. ; Weissman, M. M. ; Willemsen, G. ; Yang, J. ; Zhao, W. ; Tiemeier, H. (Corresponding author) ; Sullivan, P. F.

2017
Elsevier Science Amsterdam [u.a.]

Biological psychiatry 82(5), 322-329 (2017) [10.1016/j.biopsych.2016.11.013]

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Please use a persistent id in citations: doi:10.1016/j.biopsych.2016.11.013

Abstract: BackgroundThe 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.MethodsWe 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.ResultsThe 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 × 10–9) 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 × 10–9).ConclusionsThis 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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