| Title: | Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations |
| Journal: | Nature Communications |
| Published: | 6 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41651857/ |
| DOI: | https://doi.org/10.1038/s41467-026-69208-3 |
| URL: | https://www.nature.com/articles/s41467-026-69208-3_reference.pdf |
Publication 18346
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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.</p>
16 Keywords
- Adult
- Aged
- Anthropometry
- Body Height
- Body Mass Index
- Female
- Fibroblast Growth Factors
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
- United Kingdom
- Waist-Hip Ratio
- Whole Genome Sequencing
12 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 103356 | Understanding the role of rare and common genetic variation in human phenotypes |
Enabling scientific discoveries that improve human health