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

  • Author(s): Singh, Tarjinder
  • Kurki, Mitja I
  • Curtis, David
  • Purcell, Shaun M
  • Crooks, Lucy
  • McRae, Jeremy
  • Suvisaari, Jaana
  • Chheda, Himanshu
  • Blackwood, Douglas
  • Breen, Gerome
  • Pietiläinen, Olli
  • Gerety, Sebastian S
  • Ayub, Muhammad
  • Blyth, Moira
  • Cole, Trevor
  • Collier, David
  • Coomber, Eve L
  • Craddock, Nick
  • Daly, Mark J
  • Danesh, John
  • DiForti, Marta
  • Foster, Alison
  • Freimer, Nelson B
  • Geschwind, Daniel
  • Johnstone, Mandy
  • Joss, Shelagh
  • Kirov, Georg
  • Körkkö, Jarmo
  • Kuismin, Outi
  • Holmans, Peter
  • Hultman, Christina M
  • Iyegbe, Conrad
  • Lönnqvist, Jouko
  • Männikkö, Minna
  • McCarroll, Steve A
  • McGuffin, Peter
  • McIntosh, Andrew M
  • McQuillin, Andrew
  • Moilanen, Jukka S
  • Moore, Carmel
  • Murray, Robin M
  • Newbury-Ecob, Ruth
  • Ouwehand, Willem
  • Paunio, Tiina
  • Prigmore, Elena
  • Rees, Elliott
  • Roberts, David
  • Sambrook, Jennifer
  • Sklar, Pamela
  • St Clair, David
  • Veijola, Juha
  • Walters, James TR
  • Williams, Hywel
  • Swedish Schizophrenia Study
  • INTERVAL Study
  • DDD Study
  • UK10 K Consortium
  • Sullivan, Patrick F
  • Hurles, Matthew E
  • O'Donovan, Michael C
  • Palotie, Aarno
  • Owen, Michael J
  • Barrett, Jeffrey C
  • et al.

Published Web Location

https://doi.org/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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