Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height

Nat Commun. 2024 Oct 3;15(1):8549. doi: 10.1038/s41467-024-52579-w.

Abstract

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < 6 × 10 - 10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.

MeSH terms

  • Body Height* / genetics
  • Female
  • Gene Frequency
  • Genetic Variation
  • Genome, Human
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Whole Genome Sequencing*