Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease
Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease
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DOI：
10.1186/s13073-020-00772-z
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发表时间：
2020-08-28
期刊：
影响因子：
12.3
通讯作者：
Brunak, Soren
中科院分区：
文献类型：
--
作者：
Izarzugaza, Jose M. G.;Ellesoe, Sabrina G.;Brunak, Soren
先天性心脏病（CHD）发生在近1%的新生儿中，被认为是一种多因素疾病。冠心病可能在家庭中分离，由于疾病病因中的遗传因素的显着贡献。这项研究的目的是确定冠心病家族分离的病理生理机制。方法：我们使用全外显子组测序，以确定罕见的遗传变异，在90个同意参与者从32个丹麦家庭复发冠心病。我们应用系统生物学方法来确定罕见变异积累影响的发育机制。我们使用了一个独立的队列的714例冠心病病例和4922对照复制和斑马鱼作为体内模型进行功能研究。结果我们鉴定了1785个基因，其中罕见的等位基因在一个家庭中的患病个体之间共享。这些基因富含已知的心脏发育基因，其中218个基因在一个以上的家族中发生突变。我们的分析揭示了一个功能簇，富含已知参与钙信号传导的蛋白质。一项独立队列研究证实了CHD患者钙信号基因突变负荷增加。对ITPR 1、PLCB 2和ADCY 2的斑马鱼直系同源基因的功能研究证实了其在心脏发育中的作用，并表明这些基因失活的组合效应。结论钙信号异常是冠心病发病的一种新的病理生理机制，并证实了冠心病复杂的遗传结构。
Background Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD. Methods We used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach to identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model. Results We identified 1785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes, and 218 of these genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signaling. Replication in an independent cohort confirmed increased mutation burden of calcium-signaling genes in CHD patients. Functional investigation of zebrafish orthologues ofITPR1,PLCB2, andADCY2verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes. Conclusions The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.