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

Tarjinder Singh, Mitja I. Kurki, David Curtis, Shaun M. Purcell, Lucy Crooks, Jeremy McRae, Jaana Suvisaari, Himanshu Chheda, Douglas Blackwood, Gerome Breen, Olli Pietilinen, Sebastian S. Gerety, Muhammad Ayub, Moira Blyth, Trevor Cole, David Collier, Eve L. Coomber, Nick Craddock, Mark J. Daly, John DaneshMarta DiForti, Alison Foster, Nelson B. Freimer, Daniel Geschwind, Mandy Johnstone, Shelagh Joss, Georg Kirov, Jarmo Körkkö, Outi Kuismin, Peter Holmans, Christina M. Hultman, Conrad Iyegbe, Jouko Lönnqvist, Minna Mnnikkö, Steve A. McCarroll, Peter McGuffin, Andrew M. McIntosh, Andrew McQuillin, Jukka S. Moilanen, Carmel Moore, Robin M. Murray, Ruth Newbury-Ecob, Willem Ouwehand, Tiina Paunio, Elena Prigmore, Elliott Rees, David Roberts, Jennifer Sambrook, Pamela Sklar, David St Clair, Juha Veijola, James T.R. Walters, Hywel Williams, Patrick F. Sullivan, Matthew E. Hurles, Michael C. O'Donovan, Aarno Palotie, Michael J. Owen, Jeffrey C. Barrett*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

306 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)571-577
Number of pages7
JournalNature Neuroscience
Issue number4
Publication statusPublished - 29 Mar 2016

Bibliographical note

We thank the thousands of patients who participated in these studies. We thank H. Firth and D. FitzPatrick for discussions. The UK10K project was funded by Wellcome Trust grant WT091310. The DDD Study is funded by HICF-1009-003. The DDD and the INTERVAL sequencing studies are funded by Wellcome Trust grant WT098051. T.S. is supported by the Williams College Dr. Herchel Smith Fellowship. P.F.S. is supported by NIH R01 MH077139. A.P. is supported by Academy of Finland grants 251704 and 286500, NIMH U01MH105666 and the Sigrid Juselius Foundation. The work at Cardiff University was funded by Medical Research Council (MRC) Centre (G0801418) and Program Grants (G0800509). The key groups of the Sequencing Initiative Suomi (SISu) project are from the Universities of Eastern Finland, Oulu and Helsinki and The Institute for Health and Welfare, Finland, Lund University, The Wellcome Trust Sanger Institute, University of Oxford, The Broad Institute, University of Michigan, Washington University in St. Louis and University of California, Los Angeles (UCLA). The SiSu project is coordinated in the Institute for Molecular Medicine Finland at the University of Helsinki. Participants in INTERVAL were recruited with the active collaboration of NHS Blood and Transplant England, which has supported fieldwork and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR RP-PG-0310-1004), the NIHR BioResource and the NIHR Cambridge Biomedical Research Centre. The academic coordinating center for INTERVAL was supported by core funding from NIHR Blood and Transplant Research Unit in Donor Health and Genomics, UK Medical Research Council (G0800270) and British Heart Foundation (SP/09/002). M.I.K. was supported by Instrumentarium Science Foundation, Finland; Finnish Foundation for Cardiovascular Research; Orion Research Foundation and the University of Eastern Finland, Saastamoinen Foundation.


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