title: Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.
abstract: By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Tarjinder
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authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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authors.affiliation: University College London Genetics Institute, University College London, London, UK.
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authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Himanshu
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authors.affiliation: Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
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authors.affiliation: Institute of Psychiatry, Kings College London, London, UK.|NIHR BRC for Mental Health, Institute of Psychiatry and SLaM NHS Trust, King's College London, London, UK.
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authors.lastname: Breen
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|National Institute for Health and Welfare (THL), Helsinki, Finland.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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authors.affiliation: Institute of Psychiatry, Kings College London, London, UK.
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authors.initials: SA
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authors.affiliation: Institute of Psychiatry, Kings College London, London, UK.
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authors.affiliation: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Department of Haemotology, University of Cambridge, Cambridge, UK.|NHS Blood and Transplant, Cambridge, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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authors.initials: D
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authors.forename: Patrick F
authors.initials: PF
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Matthew E
authors.initials: ME
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authors.initials: MC
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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authors.identifier: http://orcid.org/0000-0002-1152-370X
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mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005387:Finland / Q000453:epidemiology; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D065886:Neurodevelopmental Disorders / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D012559:Schizophrenia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human