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.

Recent Advances in the Genetics of Schizophrenia

“…They found that in schizophrenia, genes intolerant of loss-of-function variation and genes whose RNAs bind FMRP, similar to CNV results, carried an excess of rare alleles with minor allele frequency less than 0.1%. The only individual gene to show study-wide significant enrichment for rare loss-of-function variants is SETD1A , specifically suggesting a role for epigenetic dysregulation in the histone H3K4 methylation in schizophrenia [86]. …”

Transcriptional Changes following Cellular Knockdown of the Schizophrenia Risk Gene <b><i>SETD1A</i></b> Are Enriched for Common Variant Association with the Disorder

“…LoF variants in SETD1A are the first findings from exome sequencing studies of schizophrenia to reach experiment-wide significance [3]. Although the role of SETD1A in regulating gene expression can be inferred through its function as a histone methyltransferase, the consequences of reduced SETD1A activity on the neural transcriptome have, to date, been unknown.…”

“…These include common genetic variants with individually weak effects on susceptibility, as well as rare variants of stronger effect. Building on earlier observations [2], a recent large-scale exome sequencing study identified loss of function (LoF) variants inthe SETD1A gene (encoding SET Domain Containing 1A) as the first exome-wide significant genetic risk factor for schizophrenia [3]. Although rare in the disorder, LoF mutations in SETD1A are substantially depleted in people without a neuropsychiatric diagnosis, identified in only 2 of 45,376 such individuals (compared to a frequency of 0.13% in schizophrenia cases) in the study of Singh et al [3].…”

“…Building on earlier observations [2], a recent large-scale exome sequencing study identified loss of function (LoF) variants inthe SETD1A gene (encoding SET Domain Containing 1A) as the first exome-wide significant genetic risk factor for schizophrenia [3]. Although rare in the disorder, LoF mutations in SETD1A are substantially depleted in people without a neuropsychiatric diagnosis, identified in only 2 of 45,376 such individuals (compared to a frequency of 0.13% in schizophrenia cases) in the study of Singh et al [3]. Furthermore, rare, heterozygous LoF mutations in SETD1A have been found in individuals diagnosed as having developmental disorders and childhood apraxia of speech [3, 4].…”

“…Although rare in the disorder, LoF mutations in SETD1A are substantially depleted in people without a neuropsychiatric diagnosis, identified in only 2 of 45,376 such individuals (compared to a frequency of 0.13% in schizophrenia cases) in the study of Singh et al [3]. Furthermore, rare, heterozygous LoF mutations in SETD1A have been found in individuals diagnosed as having developmental disorders and childhood apraxia of speech [3, 4]. …”