Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

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.; Cassa, Christopher A.; Lebo, Matthew S.; Ng, Kenney; Lander, Eric S.; Zhou, Alicia Y.; Kathiresan, Sekar; Khera, Amit V.

doi:10.1038/s41467-020-17374-3

articleNature CommunicationsAug 20, 2020GOLD OA

Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

ACAkl C. Fahed MWMinxian Wang JRJulian R. Homburger APAniruddh P. Patel AGAlexander G. Bick

Broad Institute · Harvard University · +8 more institutions

PubMed

Indexed incrossrefdoajpubmed

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…

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Topics & keywords

Topics

Keywords

Penetrance
Multifactorial Inheritance
Polygenic risk score
Disease
Genetics
Breast cancer
Biology
Quantitative trait locus

UN Sustainable Development Goals

Good health and well-being

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