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.
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We thank the research participants and employees of 23andMe for making this work possible. We thank S. Sunyaev, Y. Reshef, G. Kichaev, D. Speed, and F. Day for helpful discussions. This research has been conducted using the UK Biobank Resource (application number 16549). This research was funded by NIH grants R01 MH101244, R01 MH107649, and U01 HG009088.
N.A.F. is an employee of 23andMe, Inc.
Supplementary Figures 1–8 and 10–16, Supplementary Tables 5, 6, 8a, 10–16, 18–22, 24 and 25, and Supplementary Note (PDF 5807 kb)
Supplementary Tables 1–4, 7, 8b,c, 17 and 23 (XLSX 150 kb)
Proportion of heritability explained by the quintiles of each LD-related annotation of the baseline-LD model for each of the 62 data sets analyzed. (PDF 181 kb)
Effect size and enrichment of each annotation of the baseline-LD model in each of the 62 data sets analyzed. (XLSX 342 kb)
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Gazal, S., Finucane, H., Furlotte, N. et al. Linkage disequilibrium–dependent architecture of human complex traits shows action of negative selection. Nat Genet 49, 1421–1427 (2017). https://doi.org/10.1038/ng.3954
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