WashU weekly Neuroscience publications

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression
(2018) Nature Genetics, pp. 1-14. Article in Press. 

Wray, N.R.^{a b} , Ripke, S.^{c d e} , Mattheisen, M.^{f g h i} , Trzaskowski, M.^a , Byrne, E.M.^a , Abdellaoui, A.^j , Adams, M.J.^k , Agerbo, E.^{h l m} , Air, T.M.ⁿ , Andlauer, T.M.F.^{o p} , Bacanu, S.-A.^q , Bækvad-Hansen, M.^{h r} , Beekman, A.F.T.^s , Bigdeli, T.B.^{q t} , Binder, E.B.^{o u} , Blackwood, D.R.H.^k , Bryois, J.^v , Buttenschøn, H.N.^{g h w} , Bybjerg-Grauholm, J.^{h r} , Cai, N.^{x y} , Castelao, E.^z , Christensen, J.H.^{f g h} , Clarke, T.-K.^k , Coleman, J.I.R.^aa , Colodro-Conde, L.^ab , Couvy-Duchesne, B.^{b ac} , Craddock, N.^ad , Crawford, G.E.^{ae af} , Crowley, C.A.^ag , Dashti, H.S.^{c ah} , Davies, G.^ai , Deary, I.J.^ai , Degenhardt, F.^{aj ak} , Derks, E.M.^ab , Direk, N.^{al am} , Dolan, C.V.^j , Dunn, E.C.^{an ao ap} , Eley, T.C.^aa , Eriksson, N.^aq , Escott-Price, V.^ar , Kiadeh, F.H.F.^as , Finucane, H.K.^{at au} , Forstner, A.J.^{aj ak av aw} , Frank, J.^ax , Gaspar, H.A.^aa , Gill, M.^ay , Giusti-Rodríguez, P.^az , Goes, F.S.^ba , Gordon, S.D.^bb , Grove, J.^{f g h bc} , Hall, L.S.^{k bd} , Hannon, E.^be , Hansen, C.S.^{h r} , Hansen, T.F.^{bf bg bh} , Herms, S.^{aj ak aw} , Hickie, I.B.^bi , Hoffmann, P.^{aj ak aw} , Homuth, G.^bj , Horn, C.^bk , Hottenga, J.-J.^j , Hougaard, D.M.^{h r} , Hu, M.^bl , Hyde, C.L.^bm , Ising, M.^bn , Jansen, R.^s , Jin, F.^{bo bp} , Jorgenson, E.^bq , Knowles, J.A.^br , Kohane, I.S.^{bs bt bu} , Kraft, J.^e , Kretzschmar, W.W.^bv , Krogh, J.^bw , Kutalik, Z.^{bx by} , Lane, J.M.^{c ah bz} , Li, Y.^bv , Li, Y.^{ag az} , Lind, P.A.^ab , Liu, X.^bp , Lu, L.^bp , MacIntyre, D.J.^{ca cb} , MacKinnon, D.F.^ba , Maier, R.M.^b , Maier, W.^cc , Marchini, J.^cd , Mbarek, H.^j , McGrath, P.^ce , McGuffin, P.^aa , Medland, S.E.^ab , Mehta, D.^{b cf} , Middeldorp, C.M.^{j cg ch} , Mihailov, E.^ci , Milaneschi, Y.^s , Milani, L.^ci , Mill, J.^be , Mondimore, F.M.^ba , Montgomery, G.W.^a , Mostafavi, S.^{cj ck} , Mullins, N.^aa , Nauck, M.^{cl cm} , Ng, B.^ck , Nivard, M.G.^j , Nyholt, D.R.^cn , O’Reilly, P.F.^aa , Oskarsson, H.^co , Owen, M.J.^cp , Painter, J.N.^ab , Pedersen, C.B.^{h l m} , Pedersen, M.G.^{h l m} , Peterson, R.E.^{q cq} , Pettersson, E.^v , Peyrot, W.J.^s , Pistis, G.^z , Posthuma, D.^{cr cs} , Purcell, S.M.^ct , Quiroz, J.A.^cu , Qvist, P.^{f g h} , Rice, J.P.^cv , Riley, B.P.^q , Rivera, M.^{aa cw} , Saeed Mirza, S.^am , Saxena, R.^{c ah bz} , Schoevers, R.^cx , Schulte, E.C.^{cy cz} , Shen, L.^bq , Shi, J.^da , Shyn, S.I.^db , Sigurdsson, E.^dc , Sinnamon, G.B.C.^dd , Smit, J.H.^s , Smith, D.J.^de , Stefansson, H.^df , Steinberg, S.^df , Stockmeier, C.A.^dg , Streit, F.^ax , Strohmaier, J.^ax , Tansey, K.E.^dh , Teismann, H.^di , Teumer, A.^dj , Thompson, W.^{h bg dk dl} , Thomson, P.A.^dm , Thorgeirsson, T.E.^df , Tian, C.^aq , Traylor, M.^dn , Treutlein, J.^ax , Trubetskoy, V.^e , Uitterlinden, A.G.^do , Umbricht, D.^dp , van der Auwera, S.^dq , van Hemert, A.M.^dr , Viktorin, A.^v , Visscher, P.M.^{a b} , Wang, Y.^{h bg dk} , Webb, B.T.^ds , Weinsheimer, S.M.^{h bg} , Wellmann, J.^di , Willemsen, G.^j , Witt, S.H.^ax , Wu, Y.^a , Xi, H.S.^dt , Yang, J.^{a b} , Zhang, F.^a , eQTLGen^fb , 23andMe^fb , Arolt, V.^du , Baune, B.T.ⁿ , Berger, K.^di , Boomsma, D.I.^j , Cichon, S.^{aj aw dv dw} , Dannlowski, U.^du , de Geus, E.C.J.^{j dx} , DePaulo, J.R.^ba , Domenici, E.^dy , Domschke, K.^dz , Esko, T.^{c ci} , Grabe, H.J.^dq , Hamilton, S.P.^ea , Hayward, C.^eb , Heath, A.C.^cv , Hinds, D.A.^aq , Kendler, K.S.^q , Kloiber, S.^{bn ec ed} , Lewis, G.^ee , Li, Q.S.^ef , Lucae, S.^bn , Madden, P.F.A.^cv , Magnusson, P.K.^v , Martin, N.G.^bb , McIntosh, A.M.^{k ai} , Metspalu, A.^{ci eg} , Mors, O.^{h eh} , Mortensen, P.B.^{g h l m} , Müller-Myhsok, B.^{o p ei} , Nordentoft, M.^{h ej} , Nöthen, M.M.^{aj ak} , O’Donovan, M.C.^cp , Paciga, S.A.^ek , Pedersen, N.L.^v , Penninx, B.W.J.H.^s , Perlis, R.H.^{ao el} , Porteous, D.J.^dm , Potash, J.B.^em , Preisig, M.^z , Rietschel, M.^ax , Schaefer, C.^bq , Schulze, T.G.^{ax ba cz en eo} , Smoller, J.W.^{an ao ap} , Stefansson, K.^{df ep} , Tiemeier, H.^{am eq er} , Uher, R.^es , Völzke, H.^dj , Weissman, M.M.^{ce et} , Werge, T.^{h bg eu} , Winslow, A.R.^{ev ew} , Lewis, C.M.^{aa ex} , Levinson, D.F.^ey , Breen, G.^{aa ez} , Børglum, A.D.^{f g h} , Sullivan, P.F.^{v az fa} , the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium^fb

^a Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
^b Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
^c Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
^d Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
^e Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany
^f Department of Biomedicine, Aarhus University, Aarhus, Denmark
^g iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark
^h iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
ⁱ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
^j Department of Biological Psychology and EMGO+ Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^k Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
^l Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark
^m National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
ⁿ Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia
^o Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
^p Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^q Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
^r Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
^s Department of Psychiatry, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, Netherlands
^t Virginia Institute for Psychiatric and Behavior Genetics, Richmond, VA, United States
^u Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
^v Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
^w Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark
^x Statistical Genomics and Systems Genetics, European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
^y Human Genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom
^z Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland
^aa MRC Social Genetic and Developmental Psychiatry Centre, King’s College London, London, United Kingdom
^ab Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
^ac Centre for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia
^ad Psychological Medicine, Cardiff University, Cardiff, United Kingdom
^ae Center for Genomic and Computational Biology, Duke University, Durham, NC, United States
^af Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, United States
^ag Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^ah Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
^ai Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
^aj Institute of Human Genetics, University of Bonn, Bonn, Germany
^ak Life & Brain Center, Department of Genomics, University of Bonn, Bonn, Germany
^al Psychiatry, Dokuz Eylul University School of Medicine, Izmir, Turkey
^am Epidemiology, Erasmus MC, Rotterdam, Netherlands
^an Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, United States
^ao Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
^ap Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, United States
^aq Research, 23andMe, Inc., Mountain View, CA, United States
^ar Neuroscience and Mental Health, Cardiff University, Cardiff, United Kingdom
^as Bioinformatics, University of British Columbia, Vancouver, BC, Canada
^at Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States
^au Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, United States
^av Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
^aw Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
^ax Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
^ay Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
^az Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^ba Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, United States
^bb Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^bc Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
^bd Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom
^be University of Exeter Medical School, Exeter, United Kingdom
^bf Danish Headache Centre, Department of Neurology, Rigshospitalet, Glostrup, Denmark
^bg Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region of Denmark, Copenhagen, Denmark
^bh iPSYCH, Lundbeck Foundation Initiative for Psychiatric Research, Copenhagen, Denmark
^bi Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
^bj Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany
^bk Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann–La Roche, Ltd, Basel, Switzerland
^bl Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States
^bm Statistics, Pfizer Global Research and Development, Groton, CT, United States
^bn Max Planck Institute of Psychiatry, Munich, Germany
^bo Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States
^bp Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, United States
^bq Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States
^br Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, United States
^bs Informatics Program, Boston Children’s Hospital, Boston, MA, United States
^bt Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^bu Department of Biomedical Informatics, Harvard Medical School, Boston, MA, United States
^bv Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
^bw Department of Endocrinology at Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark
^bx Swiss Institute of Bioinformatics, Lausanne, Switzerland
^by Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne, Lausanne, Switzerland
^bz Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, United States
^ca Mental Health, Glasgow, United Kingdom
^cb Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
^cc Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
^cd Statistics, University of Oxford, Oxford, United Kingdom
^ce Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, United States
^cf School of Psychology and Counseling, Queensland University of Technology, Brisbane, QLD, Australia
^cg Child and Youth Mental Health Service, Children’s Health Queensland Hospital and Health Service, South Brisbane, QLD, Australia
^ch Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia
^ci Estonian Genome Center, University of Tartu, Tartu, Estonia
^cj Medical Genetics, University of British Columbia, Vancouver, BC, Canada
^ck Statistics, University of British Columbia, Vancouver, BC, Canada
^cl DZHK (German Centre for Cardiovascular Research), partner site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Germany
^cm Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
^cn Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
^co Humus, Reykjavik, Iceland
^cp MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
^cq Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
^cr Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^cs Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, Netherlands
^ct Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, United States
^cu Solid Biosciences, Boston, MA, United States
^cv Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^cw Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain
^cx Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
^cy Department of Psychiatry and Psychotherapy, Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany
^cz Institute of Psychiatric Phenomics and Genomics (IPPG), Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany
^da Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
^db Behavioral Health Services, Kaiser Permanente Washington, Seattle, WA, United States
^dc Faculty of Medicine, Department of Psychiatry, University of Iceland, Reykjavik, Iceland
^dd School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
^de Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom
^df deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
^dg Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States
^dh College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
^di Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
^dj Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
^dk KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
^dl Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States
^dm Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, United Kingdom
^dn Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
^do Internal Medicine, Erasmus MC, Rotterdam, Netherlands
^dp Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Medicine Area, Roche Innovation Center Basel, F. Hoffmann–La Roche, Ltd, Basel, Switzerland
^dq Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
^dr Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands
^ds Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
^dt Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, United States
^du Department of Psychiatry, University of Münster, Munster, Germany
^dv Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany
^dw Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
^dx Amsterdam Public Health Institute, Vrije Universiteit Medical Center, Amsterdam, Netherlands
^dy Centre for Integrative Biology, Università degli Studi di Trento, Trento, Italy
^dz Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^ea Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, United States
^eb MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
^ec Centre for Addiction and Mental Health, Toronto, Ontario, Canada
^ed Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
^ee Division of Psychiatry, University College London, London, United Kingdom
^ef Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, United States
^eg Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
^eh Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, Denmark
^ei Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
^ej Mental Health Center Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
^ek Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, United States
^el Psychiatry, Harvard Medical School, Boston, MA, United States
^em Psychiatry, University of Iowa, Iowa City, IA, United States
^en Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, United States
^eo Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
^ep Faculty of Medicine, University of Iceland, Reykjavik, Iceland
^eq Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Netherlands
^er Psychiatry, Erasmus MC, Rotterdam, Netherlands
^es Psychiatry, Dalhousie University, Halifax, NS, Canada
^et Division of Epidemiology, New York State Psychiatric Institute, New York, NY, United States
^eu Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
^ev Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Cambridge, MA, United States
^ew Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ex Department of Medical and Molecular Genetics, King’s College London, London, United Kingdom
^ey Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
^ez NIHR BRC for Mental Health, King’s College London, London, United Kingdom
^fa Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Abstract
Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype. © 2018 The Author(s)

Document Type: Article in Press
Source: Scopus