Biology subjects

Douglas Blackwood

Publications and source records attributed to Douglas Blackwood.

2 recordsLinked to original sources

bioRxiv2016

Rare schizophrenia risk variants are enriched in genes shared with neurodevelopmental disorders

By meta-analyzing rare coding variants in whole-exome sequences of 4,264 schizophrenia cases and 9,343 controls, de novo mutations in 1,077 trios, and array-based copy number variant calls from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare damaging variants in a subset of 3,230 \"highly constrained\" genes previously identified as having near-complete depletion of protein truncating variants. Furthermore, rare variant enrichment analyses demonstrate that this burden is concentrated in known autism spectrum disorder risk genes, genes diagnostic of severe developmental disorders, and the autism-implicated sets of promoter targets of CHD8, and mRNA targets of FMRP. We further show that schizophrenia patients with intellectual disability have a greater enrichment of rare damaging variants in highly constrained genes and developmental disorder genes, but that a weaker but significant enrichment exists throughout the larger schizophrenia population. Combined, our results demonstrate that schizophrenia risk loci of large effect across a range of variant types implicate a common set of genes shared with broader neurodevelopmental disorders, suggesting a path forward in identifying additional risk genes in psychiatric disorders and further supporting a neurodevelopmental etiology to the pathogenesis of schizophrenia.

Genetics↗

bioRxiv2016

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 KMT2F and risk for schizophrenia. In this dataset, we observed three de novo LoF mutations, seven LoF variants in cases, and none in controls (P = 3.3x10-9). To search for LoF variants in KMT2F 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 KMT2F is significantly depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying KMT2F LoF variants also had varying degrees of learning difficulties. We further identified four KMT2F 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 KMT2F 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.

Genomics↗