Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions
| Autor: | Anthony A. Philippakis, Julian R. Homburger, Patrick T. Ellinor, Amit Khera, Eric S. Lander, Sekar Kathiresan, Alexander G. Bick, Matthew S. Lebo, Deanna Brockman, Kenney Ng, Akl C. Fahed, Cynthia L. Neben, Minxian Wang, Aniruddh P. Patel, Christopher A. Cassa, Carmen Lai, Alicia Y. Zhou |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Multifactorial Inheritance Science General Physics and Astronomy Breast Neoplasms Penetrance 02 engineering and technology Disease Familial hypercholesterolemia Coronary Artery Disease Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Breast cancer Risk Factors Genetic variation medicine Odds Ratio Humans Genetic Predisposition to Disease lcsh:Science Cancer genetics Genetic association study Aged Genetics Multidisciplinary Genome Human Case-control study General Chemistry Odds ratio Cardiovascular genetics Middle Aged 021001 nanoscience & nanotechnology medicine.disease Lynch syndrome 030104 developmental biology Case-Control Studies lcsh:Q Female 0210 nano-technology Colorectal Neoplasms Medical genomics |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-9 (2020) |
| ISSN: | 2041-1723 |
| Popis: | 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. Genetic variation predisposes to disease via monogenic and polygenic risk variants. Here, the authors assess the interplay between these types of variation on disease penetrance in 80,928 individuals. In carriers of monogenic variants, they show that disease risk is a gradient influenced by polygenic background. |
| Databáze: | OpenAIRE |
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