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

被引：288
作者：
Gazal, Steven [1 ,2 ]
Finucane, Hilary K. [1 ,2 ,3 ]
Furlotte, Nicholas A. [4 ]
Loh, Po-Ru [1 ,2 ]
Palamara, Pier Francesco [1 ,2 ]
Liu, Xuanyao [1 ,2 ]
Schoech, Armin [1 ,2 ,5 ]
Bulik-Sullivan, Brendan [2 ,6 ]
Neale, Benjamin M. [2 ,6 ,7 ]
Gusev, Alexander [1 ,2 ]
Price, Alkes L. [1 ,2 ,8 ]
机构：
[1] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA
[2] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
[3] MIT, Dept Math, Cambridge, MA 02139 USA
[4] 23andMe Inc, Mountain View, CA USA
[5] Harvard Med Sch, Dept Syst Biol, Boston, MA USA
[6] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA
[7] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA
[8] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA
来源：
NATURE GENETICS | 2017年 / 49卷 / 10期
关键词：
GENOME-WIDE ASSOCIATION; GENETIC ARCHITECTURE; PARTITIONING HERITABILITY; MISSING HERITABILITY; POSITIVE SELECTION; HUMAN MUTATION; RISK LOCI; VARIANTS; RARE; RECOMBINATION;
D O I：
10.1038/ng.3954
中图分类号：
Q3 [遗传学];
学科分类号：
071007 ; 090102 ;
摘要：
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 x 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.
引用
收藏
页码：1421 / +
页数：10
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