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Rare coding variants in ten genes confer substantial risk for schizophrenia

Author

Listed:
  • Tarjinder Singh

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard
    Broad Institute of Harvard and MIT)

  • Timothy Poterba

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • David Curtis

    (University College London
    Queen Mary University London)

  • Huda Akil

    (University of Michigan)

  • Mariam Al Eissa

    (University College London)

  • Jack D. Barchas

    (Weill Cornell Medical College)

  • Nicholas Bass

    (University College London)

  • Tim B. Bigdeli

    (SUNY Downstate College of Medicine)

  • Gerome Breen

    (Institute of Psychiatry, Psychology and Neuroscience, King’s College London)

  • Evelyn J. Bromet

    (Health Sciences Center, Stony Brook University)

  • Peter F. Buckley

    (Virginia Commonwealth University)

  • William E. Bunney

    (University of California, Irvine)

  • Jonas Bybjerg-Grauholm

    (Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Statens Serum Institut)

  • William F. Byerley

    (University of California, San Francisco)

  • Sinéad B. Chapman

    (Broad Institute of MIT and Harvard)

  • Wei J. Chen

    (National Taiwan University)

  • Claire Churchhouse

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Nicholas Craddock

    (Cardiff University)

  • Caroline M. Cusick

    (Broad Institute of MIT and Harvard)

  • Lynn DeLisi

    (Cambridge Health Alliance, Cambridge Hospital)

  • Sheila Dodge

    (Genomics Platform, Broad Institute of MIT and Harvard)

  • Michael A. Escamilla

    (Texas Tech University Health Sciences Center)

  • Saana Eskelinen

    (University of Helsinki and Helsinki University Hospital
    Mental Health Unit, National Institute for Health and Welfare)

  • Ayman H. Fanous

    (SUNY Downstate Medical Center)

  • Stephen V. Faraone

    (SUNY Upstate Medical University)

  • Alessia Fiorentino

    (University College London)

  • Laurent Francioli

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT)

  • Stacey B. Gabriel

    (Genomics Platform, Broad Institute of MIT and Harvard)

  • Diane Gage

    (Broad Institute of MIT and Harvard)

  • Sarah A. Gagliano Taliun

    (Université de Montréal
    Montréal Heart Institute)

  • Andrea Ganna

    (Massachusetts General Hospital
    University of Helsinki)

  • Giulio Genovese

    (Broad Institute of MIT and Harvard)

  • David C. Glahn

    (Boston Children’s Hospital)

  • Jakob Grove

    (Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Aarhus University
    Center for Genomics and Personalized Medicine
    Aarhus University)

  • Mei-Hua Hall

    (McLean Hospital, Harvard Medical School)

  • Eija Hämäläinen

    (University of Helsinki)

  • Henrike O. Heyne

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard
    University of Helsinki)

  • Matti Holi

    (Helsinki University Hospital, University of Helsinki)

  • David M. Hougaard

    (Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Statens Serum Institut)

  • Daniel P. Howrigan

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Hailiang Huang

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Hai-Gwo Hwu

    (National Taiwan University)

  • René S. Kahn

    (Icahn School of Medicine at Mount Sinai
    MIRECC, JP Peters VA Hospital)

  • Hyun Min Kang

    (University of Michigan)

  • Konrad J. Karczewski

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • George Kirov

    (Cardiff University)

  • James A. Knowles

    (SUNY Downstate Medical Center)

  • Francis S. Lee

    (Weill Cornell Medical College)

  • Douglas S. Lehrer

    (Wright State University)

  • Francesco Lescai

    (Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Aarhus University)

  • Dolores Malaspina

    (Icahn School of Medicine at Mount Sinai)

  • Stephen R. Marder

    (Icahn School of Medicine at Mount Sinai)

  • Steven A. McCarroll

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Andrew M. McIntosh

    (University of Edinburgh)

  • Helena Medeiros

    (SUNY Downstate Medical Center)

  • Lili Milani

    (University of Tartu)

  • Christopher P. Morley

    (SUNY Upstate Medical University
    SUNY Upstate Medical University)

  • Derek W. Morris

    (National University of Ireland)

  • Preben Bo Mortensen

    (Aarhus University)

  • Richard M. Myers

    (HudsonAlpha Institute for Biotechnology)

  • Merete Nordentoft

    (Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Copenhagen University Hospital
    University of Copenhagen)

  • Niamh L. O’Brien

    (University College London)

  • Ana Maria Olivares

    (Broad Institute of MIT and Harvard)

  • Dost Ongur

    (McLean Hospital, Harvard Medical School)

  • Willem H. Ouwehand

    (University of Cambridge)

  • Duncan S. Palmer

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Tiina Paunio

    (University of Helsinki)

  • Digby Quested

    (Oxford Health NHS Foundation Trust)

  • Mark H. Rapaport

    (Emory University)

  • Elliott Rees

    (Cardiff University)

  • Brandi Rollins

    (University of California, Irvine)

  • F. Kyle Satterstrom

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard
    Stanford University School of Medicine)

  • Alan Schatzberg

    (Massachusetts General Hospital)

  • Edward Scolnick

    (Broad Institute of MIT and Harvard)

  • Laura J. Scott

    (University of Michigan)

  • Sally I. Sharp

    (University College London)

  • Pamela Sklar

    (Icahn School of Medicine at Mount Sinai)

  • Jordan W. Smoller

    (Massachusetts General Hospital
    Harvard Medical School)

  • Janet L. Sobell

    (University of Southern California)

  • Matthew Solomonson

    (Broad Institute of Harvard and MIT)

  • Eli A. Stahl

    (Icahn School of Medicine at Mount Sinai)

  • Christine R. Stevens

    (Broad Institute of MIT and Harvard
    Broad Institute of Harvard and MIT)

  • Jaana Suvisaari

    (Finnish Institute for Health and Welfare)

  • Grace Tiao

    (Broad Institute of Harvard and MIT)

  • Stanley J. Watson

    (University of Michigan)

  • Nicholas A. Watts

    (Broad Institute of Harvard and MIT)

  • Douglas H. Blackwood

    (University of Edinburgh)

  • Anders D. Børglum

    (Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Aarhus University
    Center for Genomics and Personalized Medicine)

  • Bruce M. Cohen

    (McLean Hospital, Harvard Medical School)

  • Aiden P. Corvin

    (Trinity College Dublin)

  • Tõnu Esko

    (University of Tartu)

  • Nelson B. Freimer

    (Karolinska Institutet)

  • Stephen J. Glatt

    (SUNY Upstate Medical University)

  • Christina M. Hultman

    (Johns Hopkins University)

  • Andrew McQuillin

    (University College London)

  • Aarno Palotie

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard
    Broad Institute of Harvard and MIT
    University of Helsinki)

  • Carlos N. Pato

    (SUNY Downstate College of Medicine)

  • Michele T. Pato

    (SUNY Downstate College of Medicine)

  • Ann E. Pulver

    (Johns Hopkins University)

  • David Clair

    (University of Aberdeen)

  • Ming T. Tsuang

    (University of California, San Diego)

  • Marquis P. Vawter

    (University of California, Irvine)

  • James T. Walters

    (Cardiff University)

  • Thomas M. Werge

    (Lundbeck Foundation Initiative for Integrative Psychiatric Research
    University of Copenhagen
    Copenhagen University Hospital
    University of Copenhagen)

  • Roel A. Ophoff

    (University of California, Los Angeles
    Erasmus University)

  • Patrick F. Sullivan

    (Karolinska Institute
    University of North Carolina)

  • Michael J. Owen

    (Cardiff University)

  • Michael Boehnke

    (University of Michigan)

  • Michael C. O’Donovan

    (Cardiff University)

  • Benjamin M. Neale

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard
    Broad Institute of Harvard and MIT)

  • Mark J. Daly

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard
    Broad Institute of Harvard and MIT
    University of Helsinki)

Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P

Suggested Citation

  • Tarjinder Singh & Timothy Poterba & David Curtis & Huda Akil & Mariam Al Eissa & Jack D. Barchas & Nicholas Bass & Tim B. Bigdeli & Gerome Breen & Evelyn J. Bromet & Peter F. Buckley & William E. Bunn, 2022. "Rare coding variants in ten genes confer substantial risk for schizophrenia," Nature, Nature, vol. 604(7906), pages 509-516, April.
    • Handle: RePEc:nat:nature:v:604:y:2022:i:7906:d:10.1038_s41586-022-04556-w
    DOI: 10.1038/s41586-022-04556-w
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    Citations

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    Cited by:

    1. Dick Schijven & Sourena Soheili-Nezhad & Simon E. Fisher & Clyde Francks, 2024. "Exome-wide analysis implicates rare protein-altering variants in human handedness," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Ralda Nehme & Olli Pietiläinen & Mykyta Artomov & Matthew Tegtmeyer & Vera Valakh & Leevi Lehtonen & Christina Bell & Tarjinder Singh & Aditi Trehan & John Sherwood & Danielle Manning & Emily Peirent , 2022. "The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    3. Sheng Wang & Belinda Wang & Vanessa Drury & Sam Drake & Nawei Sun & Hasan Alkhairo & Juan Arbelaez & Clif Duhn & Vanessa H. Bal & Kate Langley & Joanna Martin & Pieter J. Hoekstra & Andrea Dietrich & , 2023. "Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Rebecca Sebastian & Kang Jin & Narciso Pavon & Ruby Bansal & Andrew Potter & Yoonjae Song & Juliana Babu & Rafael Gabriel & Yubing Sun & Bruce Aronow & ChangHui Pak, 2023. "Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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