Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection

Nat Commun. 2019 Feb 15;10(1):790. doi: 10.1038/s41467-019-08424-6.

Abstract

Understanding the role of rare variants is important in elucidating the genetic basis of human disease. Negative selection can cause rare variants to have larger per-allele effect sizes than common variants. Here, we develop a method to estimate the minor allele frequency (MAF) dependence of SNP effect sizes. We use a model in which per-allele effect sizes have variance proportional to [p(1 - p)]α, where p is the MAF and negative values of α imply larger effect sizes for rare variants. We estimate α for 25 UK Biobank diseases and complex traits. All traits produce negative α estimates, with best-fit mean of -0.38 (s.e. 0.02) across traits. Despite larger rare variant effect sizes, rare variants (MAF < 1%) explain less than 10% of total SNP-heritability for most traits analyzed. Using evolutionary modeling and forward simulations, we validate the α model of MAF-dependent trait effects and assess plausible values of relevant evolutionary parameters.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Alleles
  • Biological Specimen Banks*
  • Gene Frequency
  • Genome-Wide Association Study / methods*
  • Genotype
  • Humans
  • Models, Genetic
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait, Heritable*
  • Selection, Genetic*
  • United Kingdom