| Title: | Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions |
| Journal: | Nature Communications |
| Published: | 20 Aug 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32820175/ |
| DOI: | https://doi.org/10.1038/s41467-020-17374-3 |
| URL: | https://www.nature.com/articles/s41467-020-17374-3.pdf |
| Citations: | 309 (125 in last 2 years) as of 8 Aug 2024 |
Publication 3362
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Abstract
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.</p>
17 Authors
- Akl C. Fahed
- Minxian Wang
- Julian R. Homburger
- Aniruddh P. Patel
- Alexander G. Bick
- Cynthia L. Neben
- Carmen Lai
- Deanna Brockman
- Anthony Philippakis
- Patrick T. Ellinor
- Christopher A. Cassa
- Matthew Lebo
- Kenney Ng
- Eric S. Lander
- Alicia Y. Zhou
- Sekar Kathiresan
- Amit V. Khera
1 Application
| Application ID | Title |
|---|---|
| 7089 | Exome Sequencing of All Premature Coronary Artery Disease Participants in UK Biobank |
Enabling scientific discoveries that improve human health