Accurate estimation of SNP-heritability from biobank-scale data irrespective of genetic architecture

Nat Genet. 2019 Aug;51(8):1244-1251. doi: 10.1038/s41588-019-0465-0. Epub 2019 Jul 29.

Abstract

SNP-heritability is a fundamental quantity in the study of complex traits. Recent studies have shown that existing methods to estimate genome-wide SNP-heritability can yield biases when their assumptions are violated. While various approaches have been proposed to account for frequency- and linkage disequilibrium (LD)-dependent genetic architectures, it remains unclear which estimates reported in the literature are reliable. Here we show that genome-wide SNP-heritability can be accurately estimated from biobank-scale data irrespective of genetic architecture, without specifying a heritability model or partitioning SNPs by allele frequency and/or LD. We show analytically and through extensive simulations starting from real genotypes (UK Biobank, N = 337 K) that, unlike existing methods, our closed-form estimator is robust across a wide range of architectures. We provide estimates of SNP-heritability for 22 complex traits in the UK Biobank and show that, consistent with our results in simulations, existing biobank-scale methods yield estimates up to 30% different from our theoretically-justified approach.

Publication types

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

MeSH terms

  • Biological Specimen Banks / statistics & numerical data*
  • Genome, Human*
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium*
  • Models, Theoretical*
  • Multifactorial Inheritance / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait, Heritable*