Rare loss-of-function variants in KMT2F are associated with schizophrenia and developmental disorders

Schizophrenia is a common, debilitating psychiatric disorder with a substantial genetic component. By analysing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls, and 1,077 parent-proband trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in and risk for schizophrenia. In this dataset, we observed three LoF mutations, seven LoF variants in cases, and none in controls (P = 3.3x10). To search for LoF variants in in individuals without a known neuropsychiatric diagnosis, we examined the exomes of 45,376 individuals in the ExAC database and found only two heterozygous LoF variants, showing that is significantly depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying LoF variants also had varying degrees of learning difficulties. We further identified four LoF carriers among 4,281 children with diverse, severe, undiagnosed developmental disorders, and two additional carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations show that LoF variants in cause a range of neurodevelopmental disorders, including schizophrenia. Combined with previous common variant evidence, we more generally implicate epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, as an important mechanism in the pathogenesis of schizophrenia.