2. Academic Validation
  3. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders

Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders

  • Nat Neurosci. 2016 Apr;19(4):571-7. doi: 10.1038/nn.4267.
Tarjinder Singh 1,  Mitja I Kurki 2 3,  David Curtis 4,  Shaun M Purcell 5,  Lucy Crooks 1 6,  Jeremy McRae 1,  Jaana Suvisaari 7,  Himanshu Chheda 2,  Douglas Blackwood 8,  Gerome Breen 9 10,  Olli Pietiläinen 1 2 7,  Sebastian S Gerety 1,  Muhammad Ayub 11,  Moira Blyth 12,  Trevor Cole 13,  David Collier 14 15,  Eve L Coomber 1,  Nick Craddock 16,  Mark J Daly 3 17,  John Danesh 1 18 19,  Marta DiForti 9,  Alison Foster 20,  Nelson B Freimer 21,  Daniel Geschwind 22,  Mandy Johnstone 8,  Shelagh Joss 23,  Georg Kirov 16,  Jarmo Körkkö 24,  Outi Kuismin 25,  Peter Holmans 16,  Christina M Hultman 26,  Conrad Iyegbe 9,  Jouko Lönnqvist 7,  Minna Männikkö 27,  Steve A McCarroll 17 28,  Peter McGuffin 9,  Andrew M McIntosh 8,  Andrew McQuillin 29,  Jukka S Moilanen 25,  Carmel Moore 18 19,  Robin M Murray 9 10,  Ruth Newbury-Ecob 30,  Willem Ouwehand 1 18 31 32,  Tiina Paunio 7 33,  Elena Prigmore 1,  Elliott Rees 16,  David Roberts 18 34 35,  Jennifer Sambrook 19 31,  Pamela Sklar 5,  David St Clair 36,  Juha Veijola 37,  James T R Walters 16,  Hywel Williams 16,  Swedish Schizophrenia Study,  INTERVAL Study,  DDD Study,  UK10 K Consortium,  Patrick F Sullivan 26 38 39,  Matthew E Hurles 1,  Michael C O'Donovan 16,  Aarno Palotie 1 2 3,  Michael J Owen 1,  Jeffrey C Barrett 1
Affiliations

Affiliations

  • 1 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
  • 2 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • 3 Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • 4 University College London Genetics Institute, University College London, London, UK.
  • 5 Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 6 Sheffield Diagnostic Genetics Service, Sheffield Childrens' NHS Foundation Trust, Sheffield, UK.
  • 7 National Institute for Health and Welfare (THL), Helsinki, Finland.
  • 8 Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
  • 9 Institute of Psychiatry, Kings College London, London, UK.
  • 10 NIHR BRC for Mental Health, Institute of Psychiatry and SLaM NHS Trust, King's College London, London, UK.
  • 11 Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, Ontario, Canada.
  • 12 Department of Clinical Genetics, Chapel Allerton Hospital, Chapeltown Road, Leeds, UK.
  • 13 Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
  • 14 Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
  • 15 Lilly Research Laboratories, Eli Lilly &Co. Ltd., Windlesham, Surrey, UK.
  • 16 MRC Centre for Neuropsychiatric Genetics &Genomics, Institute of Psychological Medicine &Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
  • 17 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • 18 NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • 19 INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • 20 Clinical Genetics Unit, Birmingham Women's NHS Foundation Trust, Edgbaston, Birmingham, UK.
  • 21 Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, California, USA.
  • 22 UCLA David Geffen School of Medicine, Los Angeles, California, USA.
  • 23 West of Scotland Genetics Service, South Glasgow University Hospitals, Glasgow, UK.
  • 24 Center for Intellectual Disability Care, Oulu University Hospital and University of Oulu, Oulu, Finland.
  • 25 PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
  • 26 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • 27 Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland.
  • 28 Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
  • 29 University College London, Molecular Psychiatry Laboratory, Division of Psychiatry, London, UK.
  • 30 Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, St Michael's Hospital, Bristol, UK.
  • 31 Department of Haemotology, University of Cambridge, Cambridge, UK.
  • 32 NHS Blood and Transplant, Cambridge, UK.
  • 33 University of Helsinki, Department of Psychiatry, Helsinki, Finland.
  • 34 NHS Blood and Transplant Oxford Centre, John Radcliffe Hospital, Oxford, UK.
  • 35 Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  • 36 Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
  • 37 Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
  • 38 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
  • 39 Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.
PMID: 26974950 DOI: 10.1038/nn.4267
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.

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