Department of Epidemiology, Human Genetics and Environmental Sciences and Human Genetics Center, UTHealth School of Public Health, Houston, Texas, United States of America.
Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2019 Jul 17;14(7):e0219926. doi: 10.1371/journal.pone.0219926. eCollection 2019.
Conotruncal heart defects (CTDs) are among the most common and severe groups of congenital heart defects. Despite evidence of an inherited genetic contribution to CTDs, little is known about the specific genes that contribute to the development of CTDs. We performed gene-based genome-wide analyses using microarray-genotyped and imputed common and rare variants data from two large studies of CTDs in the United States. We performed two case-parent trio analyses (N = 640 and 317 trios), using an extension of the family-based multi-marker association test, and two case-control analyses (N = 482 and 406 patients and comparable numbers of controls), using a sequence kernel association test. We also undertook two meta-analyses to combine the results from the analyses that used the same approach (i.e. family-based or case-control). To our knowledge, these analyses are the first reported gene-based, genome-wide association studies of CTDs. Based on our findings, we propose eight CTD candidate genes (ARF5, EIF4E, KPNA1, MAP4K3, MBNL1, NCAPG, NDFUS1 and PSMG3). Four of these genes (ARF5, KPNA1, NDUFS1 and PSMG3) have not been previously associated with normal or abnormal heart development. In addition, our analyses provide additional evidence that genes involved in chromatin-modification and in ribonucleic acid splicing are associated with congenital heart defects.
圆锥动脉干畸形（CTD）是最常见和最严重的先天性心脏缺陷之一。尽管有证据表明 CTD 具有遗传基因贡献，但对于导致 CTD 发展的特定基因知之甚少。我们使用基于微阵列基因分型和推断的常见和罕见变异数据在美国进行了两项 CTD 的全基因组基因分析。我们进行了两项病例-父母三体型分析（N = 640 和 317 个三体型），使用基于家族的多标记关联测试的扩展，以及两项病例-对照分析（N = 482 和 406 名患者和可比数量的对照），使用序列核关联测试。我们还进行了两项荟萃分析，以合并使用相同方法（即基于家族或病例对照）的分析结果。据我们所知，这些分析是首次报道的 CTD 基于基因、全基因组关联研究。基于我们的发现，我们提出了 8 个 CTD 候选基因（ARF5、EIF4E、KPNA1、MAP4K3、MBNL1、NCAPG、NDFUS1 和 PSMG3）。其中四个基因（ARF5、KPNA1、NDUFS1 和 PSMG3）以前与正常或异常心脏发育无关。此外，我们的分析还提供了额外的证据，表明涉及染色质修饰和核糖核酸剪接的基因与先天性心脏缺陷有关。
