Population-specific putative causal variants shape quantitative traits

Nat Genet. 2024 Oct;56(10):2027-2035. doi: 10.1038/s41588-024-01913-5. Epub 2024 Oct 3.

Abstract

Human genetic variants are associated with many traits through largely unknown mechanisms. Here, combining approximately 260,000 Japanese study participants, a Japanese-specific genotype reference panel and statistical fine-mapping, we identified 4,423 significant loci across 63 quantitative traits, among which 601 were new, and 9,406 putatively causal variants. New associations included Japanese-specific coding, splicing and noncoding variants, exemplified by a damaging missense variant rs730881101 in TNNT2 associated with lower heart function and increased risk for heart failure (P = 1.4 × 10-15 and odds ratio = 4.5, 95% confidence interval = 3.1-6.5). Putative causal noncoding variants were supported by state-of-art in silico functional assays and had comparable effect sizes to coding variants. A plausible example of new mechanisms of causal variants is an enrichment of causal variants in 3' untranslated regions (UTRs), including the Japanese-specific rs13306436 in IL6 associated with pro-inflammatory traits and protection against tuberculosis. We experimentally showed that transcripts with rs13306436 are resistant to mRNA degradation by regnase-1, an RNA-binding protein. Our study provides a list of fine-mapped causal variants to be tested for functionality and underscores the importance of sequencing, genotyping and association efforts in diverse populations.

MeSH terms

  • 3' Untranslated Regions / genetics
  • East Asian People / genetics
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genetics, Population*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Japan
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait Loci*
  • Ribonucleases / genetics

Substances

  • 3' Untranslated Regions
  • Ribonucleases