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Nat Commun. 2019 Feb 15;10(1):790. doi: 10.1038/s41467-019-08424-6.

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

Author information

1
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA. aschoech@hsph.harvard.edu.
2
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA. aschoech@hsph.harvard.edu.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA. aschoech@hsph.harvard.edu.
4
Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
5
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA.
6
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA.
7
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA.
8
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA.
9
Department of Biomedical Informatics, Harvard Medical School, Boston, 02115, MA, USA.
10
Department of Statistics, University of Oxford, Oxford, OX1 3LB, UK.
11
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA. aprice@hsph.harvard.edu.
12
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA. aprice@hsph.harvard.edu.
13
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA. aprice@hsph.harvard.edu.

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.

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