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Title | Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Gazal, S, Finucane, HK, Furlotte, NA, Loh, P-R, Palamara, PFrancesco, Liu, X, Schoech, A, Bulik-Sullivan, B, Neale, BM, Gusev, A, Price, AL |
Journal | Nat Genet |
Volume | 49 |
Issue | 10 |
Pagination | 1421-1427 |
Date Published | 2017 Oct |
ISSN | 1546-1718 |
Keywords | Alleles, Chi-Square Distribution, Datasets as Topic, Genetic Fitness, Genetic Variation, Humans, Linkage Disequilibrium, Models, Genetic, Molecular Sequence Annotation, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Selection, Genetic |
Abstract | 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); 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. |
DOI | 10.1038/ng.3954 |
Alternate Journal | Nat. Genet. |
PubMed ID | 28892061 |
PubMed Central ID | PMC6133304 |
Grant List | R01 MH101244 / MH / NIMH NIH HHS / United States R01 MH107649 / MH / NIMH NIH HHS / United States U01 HG009088 / HG / NHGRI NIH HHS / United States |