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Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases.

Kai YuanRyan J LongchampsAntonio F PardiñasMingrui YuTzu-Ting ChenShu-Chin LinYu ChenMax LamRuize LiuYan XiaZhenglin GuoWenzhao ShiChengguo Shennull nullMark J DalyBenjamin M NealeYen-Chen A FengYen-Feng LinChia-Yen ChenMichael O'DonovanTian GeHailiang Huang
Published in: medRxiv : the preprint server for health sciences (2023)
Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European descent has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping, which builds on the single-population fine-mapping framework, Sum of Single Effects (SuSiE). SuSiEx integrates data from an arbitrary number of ancestries, explicitly models population-specific allele frequencies and LD patterns, accounts for multiple causal variants in a genomic region, and can be applied to GWAS summary statistics when individual-level data is unavailable. We comprehensively evaluated SuSiEx using simulations, a range of quantitative traits measured in both UK Biobank and Taiwan Biobank, and schizophrenia GWAS across East Asian and European ancestries. In all evaluations, SuSiEx fine-mapped more association signals, produced smaller credible sets and higher posterior inclusion probability (PIP) for putative causal variants, and retained population-specific causal variants.
Keyphrases
  • high resolution
  • copy number
  • air pollution
  • genome wide
  • endothelial cells
  • high density
  • genome wide association
  • bipolar disorder
  • small molecule
  • dna methylation
  • climate change
  • high throughput
  • big data