Journal article
Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection
- 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)]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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 806.7KB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-019-08424-6
Authors
- Publisher:
- Nature Research
- Journal:
- Nature Communications More from this journal
- Volume:
- 10
- Article number:
- 790
- Publication date:
- 2019-02-15
- Acceptance date:
- 2019-01-09
- DOI:
- EISSN:
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2041-1723
- Pmid:
-
30770844
- Language:
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English
- Keywords:
- Pubs id:
-
pubs:974885
- UUID:
-
uuid:6169674d-26ae-465a-87de-faeecd2059c1
- Local pid:
-
pubs:974885
- Source identifiers:
-
974885
- Deposit date:
-
2019-05-24
Terms of use
- Copyright holder:
- Schoech et al
- Copyright date:
- 2019
- Notes:
- © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Licence:
- CC Attribution (CC BY)
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