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)] α , 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.
CITATION STYLE
Schoech, A. P., Jordan, D. M., Loh, P. R., Gazal, S., O’Connor, L. J., Balick, D. J., … Price, A. L. (2019). Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection. Nature Communications, 10(1). https://doi.org/10.1038/s41467-019-08424-6
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