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Nat Neurosci. 2016 Apr;19(4):571-7. doi: 10.1038/nn.4267. Epub 2016 Mar 14.

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

Author information

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.

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.

Comment in

PMID:
26974950
PMCID:
PMC6689268
DOI:
10.1038/nn.4267
[Indexed for MEDLINE]
Free PMC Article

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