Scientific article
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Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations

Published inNature communications, vol. 17, no. 1, 2432
First online date2026-02-06
Abstract

GWAS have generally focused on common variants from genotyping arrays or rare protein-coding variants from exome sequencing. Here, we use whole-genome sequencing data to evaluate the contribution to and architecture of rare non-coding variants for three commonly studied anthropometric traits: height, BMI and waist-hip ratio adjusted for BMI. Analysing 447,461 individuals in the UK Biobank for discovery and 225,515 individuals in All of Us for replication, we identify 90 rare and low-frequency single variant associations, including two independent rare variants upstream of IGF2BP2 that substantially reduce waist-hip ratio adjusted for BMI, but have distinct effects on other adiposity traits. We further identify 135 coding variant aggregates. For example, UBR3 protein-truncating variants are associated with a 2.7 kg/m2 increase in BMI. We additionally identify 51 non-coding variant aggregate associations, including one in the 5'UTR of FGF18 associated with up to 6 cm effects on height. We show that 97% of rare variant associations occur near GWAS-identified loci, demonstrating convergence of rare and common variant associations. Finally, we show that ultra rare variants explain a small fraction of heritability compared to common variants for these traits, that heritability is largely shared across ancestries, and that it concentrates around common variant loci.

Keywords
  • Quantitative trait loci
  • Gene regulation
  • Genome-wide association studies
  • Anthropometry
  • Body Height / genetics
  • Body Mass Index
  • Female
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Polymorphism, Single Nucleotide
  • UK Biobank
  • Waist-Hip Ratio
  • Whole Genome Sequencing
Funding
  • Medical Research Council [UKRI327]
  • UK Research and Innovation - Using genetics to test the disease consequences of higher adiposity uncoupled from its adverse metabolic effects [MR/T002239/1]
  • UK Research and Innovation - Genetic Evaluation of Multimorbidity towards INdividualisation of Interventions (GEMINI) [MR/W014548/1]
  • UK Research and Innovation - Using whole genome sequencing to identify non-coding elements associated with diabetes and related traits across ancestries [MR/Y003748/1]
Citation (ISO format)
HAWKES, Gareth et al. Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations. In: Nature communications, 2026, vol. 17, n° 1, p. 2432. doi: 10.1038/s41467-026-69208-3
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Additional URL for this publicationhttps://www.nature.com/articles/s41467-026-69208-3
Journal ISSN2041-1723
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