Estimation and mapping of the missing heritability of human phenotypes

Le résumé fourni par la source

Rare coding variants shape inter-individual differences in human phenotypes1. However, the contribution of rare non-coding variants to those differences remains poorly characterized. Here we analyse whole-genome sequence (WGS) data from 347,630 individuals with European ancestry in the UK Biobank2,3 to quantify the relative contribution of 40 million single-nucleotide and short indel variants (with a minor allele frequency (MAF) larger than 0.01%) to the heritability of 34 complex traits and diseases. On average across phenotypes, we find that WGS captures approximately 88% of the pedigree-based narrow sense heritability: that is, 20% from rare variants (MAF < 1%) and 68% from common variants (MAF ≥ 1%). We show that coding and non-coding genetic variants account for 21% and 79% of the rare-variant WGS-based heritability, respectively. We identified 15 traits with no significant difference between WGS-based and pedigree-based heritability estimates, suggesting their heritability is fully accounted for by WGS data. Finally, we performed genome-wide association analyses of all 34 phenotypes and, overall, identified 11,243 common-variant associations and 886 rare-variant associations. Altogether, our study provides high-precision estimates of rare-variant heritability, explains the heritability of many phenotypes and demonstrates for lipid traits that more than 25% of rare-variant heritability can be mapped to specific loci using fewer than 500,000 fully sequenced genomes. WGS data were used from 347,630 individuals with European ancestry in the UK Biobank to obtain high-precision estimates of coding and non-coding rare variant heritability for 34 complex traits and diseases.

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