Re-evaluation of SNP heritability in complex human traits

Abstract SNP heritability, the proportion of phenotypic variance explained by SNPs, has been estimated for many hundreds of traits, and these estimates are being used to explore genetic architecture and guide future research. To estimate SNP heritability requires strong assumptions about how heritability is distributed across the genome, but the assumptions in current use have not been thoroughly tested. By analyzing imputed data for 42 human traits, we empirically derive an improved model for heritability estimation. It is commonly assumed that the expected heritability of a SNP does not depend on its allele frequency; we instead identify a more realistic relationship which reflects that heritability tends to decrease with minor allele frequency. Two methods for estimating SNP heritability, GCTA and LDAK, make contrasting assumptions about how heritability varies with linkage disequilibrium; we demonstrate that the model used by LDAK better reflects the properties of real data. Additionally, we show how genotype certainty can be incorporated in the heritability model; this enables the inclusion of poorly-imputed SNPs, which can capture substantial extra heritability. Our revised method typically results in substantially higher estimates of SNP heritability: for example, across 19 traits (mainly diseases), the estimates based on common SNPs (minor allele frequency > 0.01) are on average 40% (SD 3) higher than those obtained using original GCTA, and 25% (SD 2) higher than those from the recently-proposed extension GCTA-LDMS. We conclude that for a wide range of traits, common SNPs tag a greater fraction of causal variation than is currently appreciated. When we also include rare SNPs (minor allele frequency < 0.01), we find that across 23 quantitative traits, estimates of SNP heritability increase by on average 29% (SD 12), and that rare SNPs tend to contribute about half the heritability of common SNPs.