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

被引：288

作者：

Fahed, Akl C. ^{[1
,2
,3
,4
,5
]}

Wang, Minxian ^{[4
,5
]}

Homburger, Julian R. ^{[6
]}

Patel, Aniruddh P. ^{[1
,2
,3
,4
,5
]}

Bick, Alexander G. ^{[1
,3
,4
,5
]}

Neben, Cynthia L. ^{[6
]}

Lai, Carmen ^{[6
]}

Brockman, Deanna ^{[1
,4
,5
]}

Philippakis, Anthony ^{[4
,5
]}

Ellinor, Patrick T. ^{[2
,3
,4
,5
]}

Cassa, Christopher A. ^{[7
]}

Lebo, Matthew ^{[8
]}

Ng, Kenney ^{[9
]}

Lander, Eric S. ^{[4
,5
,10
,11
]}

Zhou, Alicia Y. ^{[6
]}

Kathiresan, Sekar ^{[2
,3
,5
,12
]}

Khera, Amit V. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Massachusetts Gen Hosp, Dept Med, Ctr Genom Med, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA

[3] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Cardiovasc Dis Initiat, Cambridge, MA 02142 USA

[5] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[6] Color Genom, Burlingame, CA USA

[7] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[8] Partners HealthCare Personalized Med, Mol Med Lab, Boston, MA USA

[9] IBM Res, Ctr Computat Hlth, Cambridge, MA USA

[10] MIT, Dept Biol, Cambridge, MA USA

[11] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

[12] Verve Therapeut, Cambridge, MA USA

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

RISK PREDICTION; BREAST-CANCER; FAMILIAL HYPERCHOLESTEROLEMIA; MUTATION CARRIERS; TIME-SCALE; DISEASE; ASSOCIATION; BRCA1; IDENTIFICATION; HISTORY;

D O I：

10.1038/s41467-020-17374-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：9

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