Biology subjects

Shaun M Purcell

Publications and source records attributed to Shaun M Purcell.

3 recordsLinked to original sources

bioRxiv2016

Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

Ultra-rare inherited and de novo disruptive variants in highly constrained (HC) genes are enriched in neurodevelopmental disorders 1-5. However, their impact on cognition in the general population has not been explored. We hypothesize that disruptive and damaging ultra-rare variants (URVs) in HC genes not only confer risk to neurodevelopmental disorders, but also influence general cognitive abilities measured indirectly by years of education (YOE). We tested this hypothesis in 14,133 individuals with whole exome or genome sequencing data. The presence of one or more URVs was associated with a decrease in YOE (3.1 months less for each additional mutation; P-value=3.3x10-8) and the effect was stronger in HC genes enriched for brain expression (6.5 months less, P-value=3.4x10-5). The effect of these variants was more pronounced than the estimated effects of runs of homozygosity and pathogenic copy number variation 6-9. Our findings suggest that effects of URVs in HC genes are not confined to severe neurodevelopmental disorder, but influence the cognitive spectrum in the general population

Genetics↗

bioRxiv2016

Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia

Over 100 genetic loci harbor schizophrenia associated variants, yet how these common variants confer risk is uncertain. The CommonMind Consortium has sequenced dorsolateral prefrontal cortex RNA from schizophrenia cases (n=258) and control subjects (n=279), creating the largest publicly available resource to date of gene expression and its genetic regulation; [~]5 times larger than the latest release of GTEx. Using this resource, we find that [~]20% of the schizophrenia risk loci have common variants that could explain regulation of brain gene expression. In five loci, these variants modulate expression of a single gene: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Experimentally altered expression of three of them, FURIN, TSNARE1, and CNTN4, perturbs the proliferation and apoptotic index of neural progenitors and leads to neuroanatomical deficits in zebrafish. Furthermore, shRNA mediated knock-down of FURIN1 in neural progenitor cells derived from human induced pluripotent stem cells produces abnormal neural migration. Although 4.2% of genes (N = 693) display significant differential expression between cases and controls, 44% show some evidence for differential expression. All fold changes are [≤] 1.33, and an independent cohort yields similar differential expression for these 693 genes (r = 0.58). These findings are consistent with schizophrenia being highly polygenic, as has been reported in investigations of common and rare genetic variation. Co-expression analyses identify a gene module that shows enrichment for genetic associations and is thus relevant for schizophrenia. Taken together, these results pave the way for mechanistic interpretations of genetic liability for schizophrenia and other brain diseases.

Genomics↗

bioRxiv2014

Regulatory variants explain much more heritability than coding variants across 11 common diseases

Common variants implicated by genome-wide association studies (GWAS) of complex diseases are known to be enriched for coding and regulatory variants. We applied methods to partition the heritability explained by genotyped SNPs [Formula] across functional categories (while accounting for shared variance due to linkage disequilibrium) to genotype and imputed data for 11 common diseases. DNaseI Hypersensitivity Sites (DHS) from 218 cell-types, spanning 16% of the genome, explained an average of 79% of [Formula] (5.1x enrichment; P < 10-20); further enrichment was observed at enhancer and cell-type specific DHS elements. The enrichments were much smaller in analyses that did not use imputed data or were restricted to GWAS-associated SNPs. In contrast, coding variants, spanning 1% of the genome, explained only 8% of [Formula] enrichment; P = 5 x 10-4). We replicated these findings but found no significant contribution from rare coding variants in an independent schizophrenia cohort genotyped on GWAS and exome chips.

Genetics↗