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PMID: 28892061 Published · ppublish English Comparative Study Journal Article

Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection.

Nature genetics ·Vol. 49 ·No. 10 ·2017-10-00 ·Pages 1421-1427

Gazal S, Finucane HK, Furlotte NA, Loh PR, Palamara PF, Liu X, Schoech A, Bulik-Sullivan B, Neale BM, Gusev A, Price AL

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 × 10-104); 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.

MeSH Terms
Alleles Chi-Square Distribution Datasets as Topic Genetic Fitness Genetic Variation/genetics Humans Linkage Disequilibrium Models, Genetic Molecular Sequence Annotation Multifactorial Inheritance/genetics Polymorphism, Single Nucleotide Selection, Genetic
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Gazal Steven ORCID
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. | Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Finucane Hilary K
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. | Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. | Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Furlotte Nicholas A
23andMe, Inc., Mountain View, California, USA.
Loh Po-Ru
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. | Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Palamara Pier Francesco
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. | Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Liu Xuanyao
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. | Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Schoech Armin
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. | Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. | Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
Bulik-Sullivan Brendan
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. | Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Neale Benjamin M ORCID
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. | Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. | Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Gusev Alexander
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. | Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Price Alkes L ORCID
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. | Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. | Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3954
Published
2017-10-00
Epub
2017-00-11
Pages
1421-1427
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC6133304
Subset
IM
Grants
NIMH NIH HHS · R01 MH101244 · United States
NIMH NIH HHS · R01 MH107649 · United States
NHGRI NIH HHS · U01 HG009088 · United States
Corrections
ErratumIn
PMID: 31273336
External Links
PubMed source DOI: 10.1038/ng.3954 PMC Full Text View journal details
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