Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection

Nat Genet. 2017 Oct;49(10):1421-1427. doi: 10.1038/ng.3954. Epub 2017 Sep 11.


Recent work has hinted at the linkage disequilibrium (LD)-dependent architecture of human complex traits, where SNPs with low levels of LD (LLD) have larger per-SNP heritability. Here we analyzed summary statistics from 56 complex traits (average N = 101,401) by extending stratified LD score regression to continuous annotations. We determined that SNPs with low LLD have significantly larger per-SNP heritability and that roughly half of this effect can be explained by functional annotations negatively correlated with LLD, such as DNase I hypersensitivity sites (DHSs). The remaining signal is largely driven by our finding that more recent common variants tend to have lower LLD and to explain more heritability (P = 2.38 × 10-104); the youngest 20% of common SNPs explain 3.9 times more heritability than the oldest 20%, consistent with the action of negative selection. We also inferred jointly significant effects of other LD-related annotations and confirmed via forward simulations that they jointly predict deleterious effects.

Publication types

  • Comparative Study

MeSH terms

  • Alleles
  • Chi-Square Distribution
  • Datasets as Topic
  • Genetic Fitness
  • Genetic Variation / genetics*
  • Humans
  • Linkage Disequilibrium*
  • Models, Genetic
  • Molecular Sequence Annotation
  • Multifactorial Inheritance / genetics*
  • Polymorphism, Single Nucleotide*
  • Selection, Genetic*