“Partitioning Gene-Level Contributions to Complex-Trait Heritability by Allele Frequency Identifies Disease-Relevant Genes”, 2021-08-18 (; similar):
Recent works have shown that SNP-heritability—which is dominated by low-effect common variants—may not be the most relevant quantity for localizing high-effect/critical disease genes. Here, we introduce methods to estimate the proportion of phenotypic variance explained by a given assignment of SNPs to a single gene (gene-level heritability). We partition gene-level heritability across minor allele frequency (MAF) classes to find genes whose gene-level heritability is explained exclusively by “low-frequency/rare” variants (0.5% ≤ MAF < 1%).
Applying our method to ~17K protein-coding genes and 25 quantitative traits in the UK Biobank (n = 290K), we find that, on average across traits, ~2.5% of nonzero-heritability genes have a rare-variant component, and only ~0.8% (370 gene-trait pairs) have heritability exclusively from rare variants. Of these 370 gene-trait pairs, 37% were not detected by existing gene-level association testing methods, likely because existing methods combine signal from all variants in a region irrespective of MAF class. Many of the additional genes we identify are implicated in phenotypically related Mendelian disorders or congenital developmental disorders, providing further evidence of their trait-relevance.
Notably, the rare-variant component of gene-level heritability exhibits trends different from those of common-variant gene-level heritability. For example, while total gene-level heritability increases with gene length, the rare-variant component is larger among shorter genes; the cumulative distributions of gene-level heritability also vary across traits and reveal differences in the relative contributions of rare/common variants to overall gene-level polygenicity.
We conclude that the proportion of gene-level heritability attributable to low-frequency/rare variation can yield novel insights into complex-trait genetic architecture.