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Nat Commun DOI:10.1038/s41467-020-17374-3

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

Publication TypeJournal Article
Year of Publication2020
AuthorsFahed, AC, Wang, M, Homburger, JR, Patel, AP, Bick, AG, Neben, CL, Lai, C, Brockman, D, Philippakis, A, Ellinor, PT, Cassa, CA, Lebo, M, Ng, K, Lander, ES, Zhou, AY, Kathiresan, S, Khera, AV
JournalNat Commun
Date Published2020 08 20

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.


Alternate JournalNat Commun
PubMed ID32820175
Grant ListT32 HL007208 / HL / NHLBI NIH HHS / United States
R01 HL128914 / HL / NHLBI NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
UM1 HG008895 / HG / NHGRI NIH HHS / United States
K08 HG010155 / HG / NHGRI NIH HHS / United States
R01 HG010372 / HG / NHGRI NIH HHS / United States
Additional Materials