Population-specific causal disease effect sizes in functionally important regions impacted by selection

Nat Commun. 2021 Feb 17;12(1):1098. doi: 10.1038/s41467-021-21286-1.

Abstract

Many diseases exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We develop a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and apply S-LDXR to genome-wide summary statistics for 31 diseases and complex traits in East Asians (average N = 90K) and Europeans (average N = 267K) with an average trans-ethnic genetic correlation of 0.85. We determine that squared trans-ethnic genetic correlation is 0.82× (s.e. 0.01) depleted in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes are more population-specific in functionally important regions, including conserved and regulatory regions. In regions surrounding specifically expressed genes, causal effect sizes are most population-specific for skin and immune genes, and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms
  • Asian People / genetics
  • Genetics, Population / methods*
  • Genome-Wide Association Study / methods*
  • Genomics / methods
  • Haplotypes / genetics
  • Humans
  • Linkage Disequilibrium*
  • Models, Genetic
  • Polymorphism, Single Nucleotide*
  • Selection, Genetic*
  • White People / genetics