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.

Figure 1

Study design for the schizophrenia (SCZ) exome meta-analysis. The source of sequencing data, sample sizes, variant classes and analytical methods are described. Details on case-control samples are shown on the right and parent-proband trios are described on the left.

Figure 2

The genomic position and coding consequences of 16 SETD1A LoF variants observed in the schizophrenia exome meta-analysis, the DDD study and the SiSU project. Variants discovered in patients with schizophrenia are plotted above the gene and those discovered in individuals with other neurodevelopmental disorders (from DDD and SISu) are plotted below. Each variant is colored according to its mode of inheritance. All LoF variants appeared before the conserved SET domain, which is responsible for catalyzing methylation. Seven LoF variants occurred at the same two-base deletion at the exon 16 splice acceptor (c.4582-2delAG>-).

Figure 3

A comparison of genome-wide de novo mutation rates in probands with ASD, DD, schizophrenia (SCZ) and controls. Rates are modeled using calibrated genome-wide mutation rates. Significant excess of de novo mutations when compared to the baseline model, *P < 4 × 10−3 (Bonferroni correction for 12 tests). Nominal significance can be inferred from the error bars (95% CI). Mis, damaging missense; Syn, synonymous; see Online Methods.