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

  • Author(s): Hou, Kangcheng
  • Burch, Kathryn S
  • Majumdar, Arunabha
  • Shi, Huwenbo
  • Mancuso, Nicholas
  • Wu, Yue
  • Sankararaman, Sriram
  • Pasaniuc, Bogdan
  • et al.
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.

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