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<p>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 <i>IGF2BP2</i> 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, <i>UBR3</i> 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 <i>FGF18</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • Gareth Hawkes,
  • Harrison I. W. Wright,
  • Robin N. Beaumont,
  • Kartik Chundru,
  • Aimee Hanson,
  • Leigh Jackson,
  • Anna Murray,
  • Kashyap Patel,
  • Timothy M. Frayling,
  • Caroline F. Wright,
  • Andrew R. Wood,
  • Michael N. Weedon

摘要

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.