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

Citation:

Schoech AP, Jordan DM, Loh P-R, Gazal S, O'Connor LJ, Balick DJ, Palamara PF, Finucane HK, Sunyaev SR, Price AL. Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection. Nat Commun 2019;10(1):790.

Date Published:

2019 02 15

Abstract:

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.

Last updated on 06/02/2019