Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
41372416
TITLE
Mapping the genetic landscape across 14 psychiatric disorders.
ABSTRACT
Psychiatric disorders display high levels of comorbidity and genetic overlap , challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder , genomic methods have revealed that the majority of genetic signal is shared . While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses , the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations.
© 2025. The Author(s).
DATE PUBLISHED
2026 Jan
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2024/12/05
accepted 2025/10/28
medline 2026/01/08 00:27
pubmed 2025/12/11 01:22
entrez 2025/12/10 23:28
pmc-release 2025/12/10
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Grotzinger AD Grotzinger Andrew D AD Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA. andrew.grotzinger@colorado.edu.
Werme J Werme Josefin J Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Peyrot WJ Peyrot Wouter J WJ Department of Psychiatry, Amsterdam UMC, Amsterdam, The Netherlands.
Frei O Frei Oleksandr O NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
de Leeuw C de Leeuw Christiaan C Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Bicks LK Bicks Lucy K LK Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Guo Q Guo Qiuyu Q Discovery Biomarker, Amgen, Thousand Oaks, CA, USA.
Margolis MP Margolis Michael P MP Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Coombes BJ Coombes Brandon J BJ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Batzler A Batzler Anthony A Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Pazdernik V Pazdernik Vanessa V Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Biernacka JM Biernacka Joanna M JM Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA.
Andreassen OA Andreassen Ole A OA KG Jebsen Centre for Neurodevelopment, University of Oslo, Oslo, Norway.
Anttila V Anttila Verneri V Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Børglum AD Børglum Anders D AD The Lundbeck Foundation Initiative for Integrative Psychiatric Research-iPSYCH, Aarhus, Denmark.
Breen G Breen Gerome G Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
Cai N Cai Na N Helmholtz Pioneer Campus, Helmholtz Munich, Neuherberg, Germany.
Demontis D Demontis Ditte D The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Edenberg HJ Edenberg Howard J HJ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Faraone SV Faraone Stephen V SV Department of Psychiatry, Norton College of Medicine, SUNY Upstate Medical Universitiy, Syracuse, NY, USA.
Franke B Franke Barbara B Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
Gandal MJ Gandal Michael J MJ Lifespan Brain Institute at Penn Med and the Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Gelernter J Gelernter Joel J VA Connecticut Healthcare Center, West Haven, CT, USA.
Hatoum AS Hatoum Alexander S AS Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
Hettema JM Hettema John M JM Department of Psychiatry and Behavioral Sciences, Texas A&M University, College Station, TX, USA.
Johnson EC Johnson Emma C EC Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
Jonas KG Jonas Katherine G KG Department of Psychiatry & Behavioral Health, Stony Brook University, New York, NY, USA.
Knowles JA Knowles James A JA Human Genetics Institute of New Jersey (HGINJ), Rutgers University, Piscataway, NJ, USA.
Koenen KC Koenen Karestan C KC Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Maihofer AX Maihofer Adam X AX Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Mallard TT Mallard Travis T TT Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Mattheisen M Mattheisen Manuel M Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
Mitchell KS Mitchell Karen S KS National Center for PTSD at VA Boston Healthcare System, Boston, MA, USA.
Neale BM Neale Benjamin M BM Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Nievergelt CM Nievergelt Caroline M CM Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Nurnberger JI Nurnberger John I JI Department of Medical and Molecular Genetics, Department of Psychiatry, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
O'Connell KS O'Connell Kevin S KS NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Peterson RE Peterson Roseann E RE Department of Psychiatry and Behavioral Sciences, Institute for Genomics in Health, SUNY Downstate Health Sciences University, New York, NY, USA.
Robinson EB Robinson Elise B EB Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Sanchez-Roige SS Sanchez-Roige Sandra S SS Institute for Genomic Medicine, University of California San Diego, San Diego, CA, USA.
Santangelo SL Santangelo Susan L SL Department of Psychiatry, Tufts University School of Medicine, Boston, MA, USA.
Scharf JM Scharf Jeremiah M JM Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Stefansson H Stefansson Hreinn H Amgen-deCODE Genetics, Reykjavik, Iceland.
Stefansson K Stefansson Kari K Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
Stein MB Stein Murray B MB VA San Diego Healthcare System, San Diego, CA, USA.
Strom NI Strom Nora I NI Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
Thornton LM Thornton Laura M LM Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Tucker-Drob EM Tucker-Drob Elliot M EM Population Research Center, University of Texas at Austin, Austin, TX, USA.
Verhulst B Verhulst Brad B Department of Psychiatry and Behavioral Sciences, Texas A&M University, College Station, TX, USA.
Waldman ID Waldman Irwin D ID Department of Psychology, Emory University, Atlanta, GA, USA.
Walters GB Walters G Bragi GB Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
Wray NR Wray Naomi R NR Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Yu D Yu Dongmei D Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Anxiety Disorders Working Group of the Psychiatric Genomics Consortium
Attention-Deficit/Hyperactivity Disorder (ADHD) Working Group of the Psychiatric Genomics Consortium
Autism Spectrum Disorders Working Group of the Psychiatric Genomics Consortium
Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
Eating Disorders Working Group of the Psychiatric Genomics Consortium
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Nicotine Dependence GenOmics (iNDiGO) Consortium
Obsessive-Compulsive Disorder and Tourette Syndrome Working Group of the Psychiatric Genomics Consortium
Post-Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium
Schizophrenia Working Group of the Psychiatric Genomics Consortium
Substance Use Disorders Working Group of the Psychiatric Genomics Consortium
Lee PH Lee Phil H PH Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Kendler KS Kendler Kenneth S KS Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
Smoller JW Smoller Jordan W JW Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. jsmoller@mgb.org.
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Agrawal Arpana A
Baranger David Aa DA
Boardman Jason D JD
Boden Joseph M JM
Bogdan Ryan R
Bucholz Karhleen K KK
Choi Doo-Sup DS
Mc Colbert Sarah S
Deak Joseph D JD
Diazgranados Nancy N
Edwards Alexis C AC
Goate Alison M AM
Goldman David D
Hack Laura M LM
Harris Kathleen Mullan KM
Hartz Sarah M SM
Hayward Caroline C
Hewitt John K JK
Hopfer Christian J CJ
Karpyak Victor M VM
Krauter Kenneth S KS
Krupitsky Evgeny M EM
Kuperman Samuel S
Lahti Jari J
Lahti-Pulkkinen Marius M
Lai Dongbing D
Miller Alex P AP
Palmer Abraham A AA
Palmer Rohn H RH
Pearson John F JF
Porjesz Bernice B
Preuss Ulrich W UW
Rosenblum Daniel M DM
Scherbaum Norbert N
Vanyukov Michael M
Wall Tamara L TL
Wedow Robbee R
Weiss Stanley H SH
Wetherill Leah L
Wodarz Norbert N
Zhang Haitao H
Zhao Hongyu H
Zhou Hang H
Zill Peter P
JOURNAL
VOLUME: 649
ISSUE: 8096
TITLE: Nature
ISOABBREVIATION: Nature
YEAR: 2026
MONTH: Jan
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-4687
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nature
COUNTRY: England
ISSNLINKING: 0028-0836
NLMUNIQUEID: 0410462
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
R01 MH124851 NIMH NIH HHS United States
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R01 MH124871 NIMH NIH HHS United States
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R01 MH120219 NIMH NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Humans
Mental Disorders classification
Schizophrenia genetics
Bipolar Disorder genetics
Adult genetics
Male genetics
Depressive Disorder, Major genetics
Genome-Wide Association Study genetics
Multifactorial Inheritance genetics
Female genetics
Child genetics
Stress Disorders, Post-Traumatic genetics
Genetic Pleiotropy genetics
Genomics genetics
Genetic Predisposition to Disease genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
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