Estimation and mapping of the missing heritability of human phenotypes

Journal article

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.

Authors: Wainschtein, P; Zhang, Y; Schwartzentruber, J; Kassam, I; Sidorenko, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature
• Volume: 649
• Issue: 8099
• Pages: 1219-1227
• Publication date: 2025-11-12
• Acceptance date: 2025-10-08
• DOI: 10.1038/s41586-025-09720-6
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English