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 Danesh; Marta 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

doi:10.1038/nn.4267

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 Danesh

Marta 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

Wellcome Trust
Broad Institute of MIT and Harvard
UCL University College London
Icahn School of Medicine at Mount Sinai
Medway NHS Foundation Trust
National Institute for Health and Welfare
University of Helsinki
University of Edinburgh
King's College London
Queens University
Chapel Allerton Hospital
Birmingham Women's NHS Foundation Trust
King's College Hospital
Eli Lilly & Co Ltd
Cardiff University
University of Cambridge
University of California, Los Angeles
University of Glasgow
Oulu University Hospital
Oulun Yliopisto
Karolinska Institute
Harvard Medical School
St. Michael's Hospital
NHS Blood and Transplant
University of Oxford
University of Aberdeen
University of North Carolina at Chapel Hill

Research output: Contribution to journal › Article › peer-review

359 Citations (Scopus)

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.

Original language	English
Pages (from-to)	571-577
Number of pages	7
Journal	Nature Neuroscience
Volume	19
Issue number	4
Early online date	14 Mar 2016
DOIs	https://doi.org/10.1038/nn.4267
Publication status	Published - 29 Mar 2016

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10.1038/nn.4267

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Singh, T., Kurki, M. I., Curtis, D., Purcell, S. M., Crooks, L., McRae, J., Suvisaari, J., Chheda, H., Blackwood, D., Breen, G., Pietilinen, O., Gerety, S. S., Ayub, M., Blyth, M., Cole, T., Collier, D., Coomber, E. L., Craddock, N., Daly, M. J., ... Barrett, J. C. (2016). Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nature Neuroscience, 19(4), 571-577. https://doi.org/10.1038/nn.4267

@article{0de95a42682247d9989d47adf5dd78f5,

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.",

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

year = "2016",

month = mar,

day = "29",

doi = "10.1038/nn.4267",

language = "English",

volume = "19",

pages = "571--577",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

number = "4",

}

Singh, T, Kurki, MI, Curtis, D, Purcell, SM, Crooks, L, McRae, J, Suvisaari, J, Chheda, H, Blackwood, D, Breen, G, Pietilinen, O, Gerety, SS, Ayub, M, Blyth, M, Cole, T, Collier, D, Coomber, EL, Craddock, N, Daly, MJ, Danesh, J, DiForti, M, Foster, A, Freimer, NB, Geschwind, D, Johnstone, M, Joss, S, Kirov, G, Körkkö, J, Kuismin, O, Holmans, P, Hultman, CM, Iyegbe, C, Lönnqvist, J, Mnnikkö, M, McCarroll, SA, McGuffin, P, McIntosh, AM, McQuillin, A, Moilanen, JS, Moore, C, Murray, RM, Newbury-Ecob, R, Ouwehand, W, Paunio, T, Prigmore, E, Rees, E, Roberts, D, Sambrook, J, Sklar, P, St Clair, D, Veijola, J, Walters, JTR, Williams, H, Sullivan, PF, Hurles, ME, O'Donovan, MC, Palotie, A, Owen, MJ & Barrett, JC 2016, 'Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders', Nature Neuroscience, vol. 19, no. 4, pp. 571-577. https://doi.org/10.1038/nn.4267

TY - JOUR

T1 - Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders

AU - Singh, Tarjinder

AU - Kurki, Mitja I.

AU - Curtis, David

AU - Purcell, Shaun M.

AU - Crooks, Lucy

AU - McRae, Jeremy

AU - Suvisaari, Jaana

AU - Chheda, Himanshu

AU - Blackwood, Douglas

AU - Breen, Gerome

AU - Pietilinen, Olli

AU - Gerety, Sebastian S.

AU - Ayub, Muhammad

AU - Blyth, Moira

AU - Cole, Trevor

AU - Collier, David

AU - Coomber, Eve L.

AU - Craddock, Nick

AU - Daly, Mark J.

AU - Danesh, John

AU - DiForti, Marta

AU - Foster, Alison

AU - Freimer, Nelson B.

AU - Geschwind, Daniel

AU - Johnstone, Mandy

AU - Joss, Shelagh

AU - Kirov, Georg

AU - Körkkö, Jarmo

AU - Kuismin, Outi

AU - Holmans, Peter

AU - Hultman, Christina M.

AU - Iyegbe, Conrad

AU - Lönnqvist, Jouko

AU - Mnnikkö, Minna

AU - McCarroll, Steve A.

AU - McGuffin, Peter

AU - McIntosh, Andrew M.

AU - McQuillin, Andrew

AU - Moilanen, Jukka S.

AU - Moore, Carmel

AU - Murray, Robin M.

AU - Newbury-Ecob, Ruth

AU - Ouwehand, Willem

AU - Paunio, Tiina

AU - Prigmore, Elena

AU - Rees, Elliott

AU - Roberts, David

AU - Sambrook, Jennifer

AU - Sklar, Pamela

AU - St Clair, David

AU - Veijola, Juha

AU - Walters, James T R

AU - Williams, Hywel

AU - Sullivan, Patrick F.

AU - Hurles, Matthew E.

AU - O'Donovan, Michael C.

AU - Palotie, Aarno

AU - Owen, Michael J.

AU - Barrett, Jeffrey C.

PY - 2016/3/29

Y1 - 2016/3/29

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84962233946

U2 - 10.1038/nn.4267

DO - 10.1038/nn.4267

M3 - Article

AN - SCOPUS:84962233946

SN - 1097-6256

VL - 19

SP - 571

EP - 577

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 4

ER -

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

Abstract

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