Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions
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s41467-020-17374-3.pdf
Description
Published version
Size
926.43 KB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Fahed, Akl C
Wang, Minxian
Homburger, Julian R
Patel, Aniruddh P
Bick, Alexander G
Neben, Cynthia L
Lai, Carmen
Brockman, Deanna
Philippakis, Anthony
Ellinor, Patrick T
Date Issued
2020
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Version
Final published version
Abstract
© 2020, The Author(s). Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions — familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background — the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-020-17374-3
