Complex trait associations in rare diseases and impacts on Mendelian variant interpretation.
Complex trait associations in rare diseases and impacts on Mendelian variant interpretation.
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罕见疾病中的复杂性状关联及其对孟德尔变异解释的影响。
DOI：
10.1101/2024.01.10.24301111
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Grundberg,E
中科院分区：
文献类型：
--
作者：
Smail,Craig;Ge,Bing;Keever-Keigher,MarissaR;Schwendinger-Schreck,Carl;Cheung,Warren;Johnston,JeffreyJ;Barrett,Cassandra;GenomicAnswersforKidsConsortium;Feldman,Keith;Cohen,AnaSA;Farrow,EmilyG;Thiffault,Isabelle;Grundberg,E
新出现的证据表明，罕见疾病的发病和表型表现与常见的遗传变异有关--聚合成多基因评分(PGS)。在这里，我们在一组3059名先证者中全面绘制了1102个开源PGS的多基因易感性，这些先证者登记在儿童基因组答案(GA4K)罕见疾病研究中，揭示了罕见疾病表型与常见复杂疾病和性状的PGSS、血液蛋白水平以及脑和其他器官形态测量之间的广泛关联。利用这一资源，我们证明了与未受影响的携带者父母相比，遗传性候选疾病变异(VUS)先证者的多基因易感性增加。此外，我们显示了相关复杂性状的假定核心PGS基因中的大效应稀有变异的丰富。总体而言，我们的研究支持和扩展了先前关于罕见疾病中复杂性状关联的发现，暗示了多基因易感性是候选因果变异变量外显性的潜在机制，并为识别新的候选罕见疾病基因提供了一个框架。
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.