Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions
Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions
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DOI：
10.1038/s41467-020-17374-3
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发表时间：
2020-08-20
影响因子：
16.6
通讯作者：
Khera, Amit V.
中科院分区：
文献类型：
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作者：
Fahed, Akl C.;Wang, Minxian;Khera, Amit V.
遗传变异可通过(i)单基因风险变异破坏对疾病有重大影响的生理途径，（ii）多基因风险变异涉及在不同途径中影响很小的许多变异。很少有研究探讨单基因和多基因风险之间的相互作用。在这里，我们研究了80,928个个体，以检查多基因背景是否可以改变1级基因组条件（家族性高胆固醇血症、遗传性乳腺癌和卵巢癌以及Lynch综合征）的疾病外显率。在单基因风险变异的携带者中，我们估计基于多基因背景的疾病风险有很大的梯度——75岁时冠状动脉疾病的患病概率为17%至78%，乳腺癌为13%至76%，结肠癌为11%至80%。我们提出，考虑多基因背景可能会提高遗传单基因风险变异的个体风险估计的准确性。遗传变异通过单基因和多基因风险变异使疾病易感性。在这里，作者评估了80,928个个体中这些类型的变异对疾病外显率的相互作用。在单基因变异的携带者中，他们表明疾病风险是受多基因背景影响的梯度。
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.