Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection

被引：70

作者：

Schoech, Armin P. ^{[1
,2
,3
]}

Jordan, Daniel M. ^{[4
]}

Loh, Po-Ru ^{[3
,5
,6
]}

Gazal, Steven ^{[1
,3
]}

O'Connor, Luke J. ^{[1
,2
,3
]}

Balick, Daniel J. ^{[5
,6
,7
]}

Palamara, Pier F. ^{[8
]}

Finucane, Hilary K. ^{[3
]}

Sunyaev, Shamil R. ^{[3
,5
,6
,7
]}

Price, Alkes L. ^{[1
,2
,3
]}

机构：

[1] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[2] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[3] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[4] Icahn Sch Med Mt Sinai, Charles R Bronfman Inst Personalized Med, New York, NY 10029 USA

[5] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[6] Harvard Med Sch, Boston, MA 02115 USA

[7] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA

[8] Univ Oxford, Dept Stat, Oxford OX1 3LB, England

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

MISSING HERITABILITY; COMPLEX TRAITS; RARE VARIANTS; SCHIZOPHRENIA; SUSCEPTIBILITY; PROPORTION; EVOLUTION; DISEASE; GWAS;

D O I：

10.1038/s41467-019-08424-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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)](alpha), where p is the MAF and negative values of alpha imply larger effect sizes for rare variants. We estimate alpha for 25 UK Biobank diseases and complex traits. All traits produce negative alpha 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 alpha model of MAF-dependent trait effects and assess plausible values of relevant evolutionary parameters.

引用

页数：10

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