Polygenic architecture of rare coding variation across 394,783 exomes

Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear. In this manuscript in Nature, CGM investigators Konrad Karczewski, Elise Robinson, and Ben Neale leverage the UK biobank exomes resource to quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 exomes. In this analysis, rare coding variants explain 1.3% of phenotypic variance on average. This variance is much less than that explained by common variants-and most burden heritability is explained by ultrarare loss-of-function variants (allele frequency < 1 × 10-5). Overall, the results indicate that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.

Read more in Nature

February 20, 2023


CGM Primary Investigators