Genomic Medicine Center, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, USA.
UKMC School of Medicine, University of Missouri Kansas City, Kansas City, USA.
Nat Commun. 2024 Sep 18;15(1):8196. doi: 10.1038/s41467-024-52407-1.
Emerging evidence implicates common genetic variation - aggregated into polygenic scores (PGS) - in the onset and phenotypic presentation of rare diseases. Here, we comprehensively map individual polygenic liability for 1102 open-source PGS in a cohort of 3059 probands enrolled in the Genomic Answers for Kids (GA4K) rare disease study, revealing widespread associations between rare disease phenotypes and PGSs for common complex diseases and traits, blood protein levels, and brain and other organ morphological measurements. Using this resource, we demonstrate increased polygenic liability in probands with an inherited candidate disease variant (VUS) compared to unaffected carrier parents. Further, we show an enrichment for large-effect rare variants in putative core PGS genes for associated complex traits. Overall, our study supports and expands on previous findings of complex trait associations in rare diseases, implicates polygenic liability as a potential mechanism underlying variable penetrance of candidate causal variants, and provides a framework for identifying novel candidate rare disease genes.
越来越多的证据表明，常见的遗传变异——聚合为多基因评分（PGS）——与罕见疾病的发病和表型表现有关。在这里，我们在 Genomic Answers for Kids（GA4K）罕见病研究中招募的 3059 名先证者队列中全面绘制了 1102 个开源 PGS 的个体多基因易感性，揭示了罕见疾病表型与常见复杂疾病和特征、血液蛋白水平以及大脑和其他器官形态测量值的 PGS 之间的广泛关联。利用这一资源，我们证明与未受影响的携带者父母相比，携带遗传候选疾病变异（VUS）的先证者具有更高的多基因易感性。此外，我们还显示了与相关复杂特征的潜在核心 PGS 基因相关的大效应罕见变异的富集。总的来说，我们的研究支持并扩展了先前关于罕见疾病中复杂特征关联的发现，表明多基因易感性是候选因果变异可变外显率的潜在机制，并为识别新的候选罕见疾病基因提供了框架。
