@article {48,
	title = {Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection.},
	journal = {Nat Commun},
	volume = {10},
	year = {2019},
	month = {2019 Feb 15},
	pages = {790},
	abstract = {<p>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.</p>},
	keywords = {Algorithms, Alleles, Biological Specimen Banks, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Models, Genetic, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Selection, Genetic, United Kingdom},
	issn = {2041-1723},
	doi = {10.1038/s41467-019-08424-6},
	author = {Schoech, Armin P and Jordan, Daniel M and Loh, Po-Ru and Gazal, Steven and O{\textquoteright}Connor, Luke J and Balick, Daniel J and Palamara, Pier F and Finucane, Hilary K and Sunyaev, Shamil R and Price, Alkes L}
}
@article {38,
	title = {Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection.},
	journal = {Nat Genet},
	volume = {49},
	year = {2017},
	month = {2017 Oct},
	pages = {1421-1427},
	abstract = {<p>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 {\texttimes} 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.</p>},
	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},
	issn = {1546-1718},
	doi = {10.1038/ng.3954},
	author = {Gazal, Steven and Finucane, Hilary K and Furlotte, Nicholas A and Loh, Po-Ru and Palamara, Pier Francesco and Liu, Xuanyao and Schoech, Armin and Bulik-Sullivan, Brendan and Neale, Benjamin M and Gusev, Alexander and Price, Alkes L}
}
