Polygenic architecture of rare coding variation across 394,783 exomes.

Area of Science:

• Genetics
• Genomics
• Complex Traits

Background:

• Common and rare genetic variants both influence complex traits and diseases.
• Genome-wide association studies (GWAS) have identified many common-variant associations, while exome sequencing reveals rare-variant associations.
• The genetic architecture of rare variants and their relationship with common variants remain incompletely understood.

Purpose of the Study:

• To quantify the heritability explained by gene-wise burdens of rare coding variants across 22 common traits and diseases.
• To compare the architecture and effects of rare versus common genetic variants.
• To investigate the mechanistic convergence between common and rare variant associations.

Main Methods:

• Analysis of 394,783 UK Biobank exomes.
• Quantification of heritability explained by rare coding variants (allele frequency < 1x10^-3).
• Comparison of heritability contributions from common variants, rare variants, and ultrarare loss-of-function variants.

Main Results:

• Rare coding variants explain 1.3% of phenotypic variance on average, significantly less than common variants.
• Ultrarare loss-of-function variants contribute most to rare variant heritability.
• Common and rare variants implicate similar cell types, show pleiotropic effects on shared traits, and partially colocalize at genes and loci.
• Burden heritability is concentrated in significant and constrained genes, whereas common-variant heritability is more polygenic.
• Burden heritability for schizophrenia and bipolar disorder is approximately 2%.

Conclusions:

• Rare coding variants implicate a manageable number of large-effect genes.
• Common and rare genetic associations are mechanistically convergent.
• Rare coding variants contribute modestly to missing heritability and population risk stratification.