GENOME-WIDE ASSOCIATION ANALYSES IDENTIFY 44 RISK VARIANTS AND REFINE THE GENETIC ARCHITECTURE OF MAJOR DEPRESSIVE DISORDER

作者：N. Wray, S. Ripke, M. Mattheisen, M. Trzaskowski, E. Byrne, A. Abdellaoui, M. Adams, E. Agerbo, Tracy M. Air, Till F. M. Andlauer, S. Bacanu, Marie Bækvad-Hansen, A. Beekman, T. Bigdeli, E. Binder, D. Blackwood, J. Bryois, H. Buttenschøn, J. Bybjerg-Grauholm, N. Cai, E. Castelao, J. Christensen, Toni‐Kim Clarke, J. Coleman, L. Colodro-Conde, B. Couvy-Duchesne, N. Craddock, G. Crawford, Cheynna A. Crowley, H. Dashti, G. Davies, I. Deary, F. Degenhardt, E. Derks, N. Direk, C. Dolan, E. Dunn, T. Eley, N. Eriksson, V. Escott-Price, Farnush Farhadi Hassan Kiadeh, H. Finucane, A. Forstner, J. Frank, Héléna A. Gaspar, M. Gill, Paola Giusti-Rorínguez, F. Goes, S. Gordon, J. Grove, L. Hall, C. Hansen, T. Hansen, S. Herms, I. Hickie, P. Hoffmann, G. Homuth, Carsten Horn, J. Hottenga, D. Hougaard, Ming Hu, C. Hyde, M. Ising, R. Jansen, Fulai Jin, E. Jorgenson, J. Knowles, I. Kohane, J. Kraft, Warren W. Kretzschmar, J. Krogh, Z. Kutalik, J. Lane, Yihan Li, Yun Li, P. Lind, Xiaoxiao Liu, Leina Lu, D. Macintyre, D. MacKinnon, Robert M. Maier, W. Maier, J. Marchini, H. Mbarek, Patrick J. McGrath, P. McGuffin, S. Medland, D. Mehta, C. Middeldorp, E. Mihailov, Y. Milaneschi, L. Milani, Francis M. Mondimore, G. Montgomery, S. Mostafavi, N. Mullins, M. Nauck, B. Ng, M. Nivard, D. Nyholt, P. O’Reilly, H. Oskarsson, M. Owen, J. Painter, Carsten Bøcker, M. Pedersen, Roseann E. Peterson, E. Pettersson, W. Peyrot, G. Pistis, D. Posthuma, S. Purcell, J. Quiroz, P. Qvist, John P. Rice, B. Riley, M. Rivera, S. Mirza, R. Saxena, R. Schoevers, E. Schulte, Ling Shen, Jianxin Shi, S. Shyn, E. Sigurdsson, Grant C. B. Sinnamon, J. Smit, Danny J. Smith, H. Stefánsson, S. Steinberg, C. Stockmeier, F. Streit, J. Strohmaier, K. Tansey, H. Teismann, A. Teumer, Wesley Thompson, P. Thomson, T. Thorgeirsson, C. Tian, M. Traylor, J. Treutlein, V. Trubetskoy, A. Uitterlinden, D. Umbricht, S. Auwera, A. M. Hemert, A. Viktorin, P. Visscher, Yunpeng Wang, B. Webb, S.M. Weinsheimer, J. Wellmann, G. Willemsen, S. Witt, Yang Wu, H. Xi, Jian Yang, Futao Zhang, V. Arolt, B. Baune, K. Berger, D. Boomsma, S. Cichon, U. Dannlowski, E. D. de Geus, J. DePaulo, E. Domenici, K. Domschke, T. Esko, H. Grabe, S. Hamilton, C. Hayward, A. Heath, D. Hinds, K. Kendler, S. Kloiber, G. Lewis, Qingqin S. Li, S. Lucae, P. Madden, P. Magnusson, N. G. Martin, A. McIntosh, A. Metspalu, O. Mors, P. Mortensen, B. Müller-Myhsok, M. Nordentoft, M. Nöthen, M. O’Donovan, S. Paciga, N. Pedersen, B. Penninx, R. Perlis, D. Porteous, J. Potash, M. Preisig, M. Rietschel, C. Schaefer, T. Schulze, J. Smoller, K. Stefánsson, H. Tiemeier, R. Uher, H. Völzke, M. Weissman, T. Werge, A. Winslow, C. Lewis, D. Levinson, G. Breen, A. Børglum, P. Sullivan · 发表于：European Neuropsychopharmacology · 年份：2019 · DOI：10.1016/J.EURONEURO.2017.08.044 · 被引用次数：68 · 研究领域：Medicine

Background Major Depressive Disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%. It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide. MDD is a major cause of disability worldwide. Twin studies attribute ~40% of the variation in liability to MDD to additive genetic effects, and may be greater for recurrent, early-onset, and postpartum MDD. GWA studies of MDD have had notable difficulties in identifying loci. Previous findings suggest that an appropriately designed study should identify susceptibility loci. Methods We conducted a Genome-Wide Association (GWA) meta-analysis in 130,664 MDD cases and 330,470 controls. We used the standard GWA mega/meta-analysis methods of the core PGC quality control, imputation, and analysis pipeline (i.e., "ricopili") Results We identified 44 independent loci that met criteria for statistical significance. We can make a strong case for the identification of RBFOX1 and NEGR1. The genetic findings were associated with clinical features of MDD, and implicated prefrontal and anterior cingulate cortex in the pathophysiology of MDD (regions exhibiting anatomical differences in MDD cases vs controls). Genes that are targets of antidepressant medications were strongly enriched for MDD association signals (P=8.5e-10), suggesting the relevance of these findings for improved pharmacotherapy of MDD. Sets of genes involved in gene spl...