%0 Journal Article %J Nat Commun %D 2019 %T Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection. %A Schoech, Armin P %A Jordan, Daniel M %A Loh, Po-Ru %A Gazal, Steven %A O'Connor, Luke J %A Balick, Daniel J %A Palamara, Pier F %A Finucane, Hilary K %A Sunyaev, Shamil R %A Price, Alkes L %K Algorithms %K Alleles %K Biological Specimen Banks %K Gene Frequency %K Genome-Wide Association Study %K Genotype %K Humans %K Models, Genetic %K Polymorphism, Single Nucleotide %K Quantitative Trait, Heritable %K Selection, Genetic %K United Kingdom %X

Understanding the role of rare variants is important in elucidating the genetic basis of human disease. Negative selection can cause rare variants to have larger per-allele effect sizes than common variants. Here, we develop a method to estimate the minor allele frequency (MAF) dependence of SNP effect sizes. We use a model in which per-allele effect sizes have variance proportional to [p(1 - p)], where p is the MAF and negative values of α imply larger effect sizes for rare variants. We estimate α for 25 UK Biobank diseases and complex traits. All traits produce negative α estimates, with best-fit mean of -0.38 (s.e. 0.02) across traits. Despite larger rare variant effect sizes, rare variants (MAF < 1%) explain less than 10% of total SNP-heritability for most traits analyzed. Using evolutionary modeling and forward simulations, we validate the α model of MAF-dependent trait effects and assess plausible values of relevant evolutionary parameters.

%B Nat Commun %V 10 %P 790 %8 2019 02 15 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30770844?dopt=Abstract %R 10.1038/s41467-019-08424-6 %0 Journal Article %J Nat Genet %D 2017 %T Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection. %A Gazal, Steven %A Finucane, Hilary K %A Furlotte, Nicholas A %A Loh, Po-Ru %A Palamara, Pier Francesco %A Liu, Xuanyao %A Schoech, Armin %A Bulik-Sullivan, Brendan %A Neale, Benjamin M %A Gusev, Alexander %A Price, Alkes L %K Alleles %K Chi-Square Distribution %K Datasets as Topic %K Genetic Fitness %K Genetic Variation %K Humans %K Linkage Disequilibrium %K Models, Genetic %K Molecular Sequence Annotation %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %K Selection, Genetic %X

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.

%B Nat Genet %V 49 %P 1421-1427 %8 2017 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/28892061?dopt=Abstract %R 10.1038/ng.3954