PT - JOURNAL ARTICLE AU - Steven Gazal AU - Hilary K. Finucane AU - Nicholas A Furlotte AU - Po-Ru Loh AU - Pier Francesco Palamara AU - Xuanyao Liu AU - Armin Schoech AU - Brendan Bulik-Sullivan AU - Benjamin M Neale AU - Alexander Gusev AU - Alkes L. Price TI - Linkage disequilibrium dependent architecture of human complex traits reveals action of negative selection AID - 10.1101/082024 DP - 2017 Jan 01 TA - bioRxiv PG - 082024 4099 - http://biorxiv.org/content/early/2017/04/03/082024.short 4100 - http://biorxiv.org/content/early/2017/04/03/082024.full AB - 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 after conditioning on their minor allele frequency (MAF). However, this has not been formally assessed, quantified or biologically interpreted. Here, we analyzed summary statistics from 56 complex diseases and 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. Roughly half of the LLD signal can be explained by functional annotations that are negatively correlated with LLD, such as DNase I hypersensitivity sites (DHS). The remaining signal is largely driven by our finding that common variants that are more recent tend to have lower LLD and to explain more heritability (P = 2.38 × 10−104); the youngest 20% of common SNPs explain 3.9x 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 these annotations jointly predict deleterious effects. Our results are consistent with the action of negative selection on deleterious variants that affect complex traits, complementing efforts to learn about negative selection by analyzing much smaller rare variant data sets.