Dataset Information

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.

SUBMITTER: Singh T

PROVIDER: S-EPMC6689268 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Singh Tarjinder T Kurki Mitja I MI Curtis David D Purcell Shaun M SM Crooks Lucy L McRae Jeremy J Suvisaari Jaana J Chheda Himanshu H Blackwood Douglas D Breen Gerome G Pietiläinen Olli O Gerety Sebastian S SS Ayub Muhammad M Blyth Moira M Cole Trevor T Collier David D Coomber Eve L EL Craddock Nick N Daly Mark J MJ Danesh John J DiForti Marta M Foster Alison A Freimer Nelson B NB Geschwind Daniel D Johnstone Mandy M Joss Shelagh S Kirov Georg G Körkkö Jarmo J Kuismin Outi O Holmans Peter P Hultman Christina M CM Iyegbe Conrad C Lönnqvist Jouko J Männikkö Minna M McCarroll Steve A SA McGuffin Peter P McIntosh Andrew M AM McQuillin Andrew A Moilanen Jukka S JS Moore Carmel C Murray Robin M RM Newbury-Ecob Ruth R Ouwehand Willem W Paunio Tiina T Prigmore Elena E Rees Elliott E Roberts David D Sambrook Jennifer J Sklar Pamela P St Clair David D Veijola Juha J Walters James T R JT Williams Hywel H Sullivan Patrick F PF Hurles Matthew E ME O'Donovan Michael C MC Palotie Aarno A Owen Michael J MJ Barrett Jeffrey C JC

Nature neuroscience 20160314 4

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 sch ...[more]

PMID: 26974950

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Project description:BackgroundRare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ.MethodsTo discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling.ResultsThrough mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal.ConclusionsThe combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.

Dataset Information

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

Publications

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

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