State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
Clin Genet. 2018 Oct;94(3-4):296-302. doi: 10.1111/cge.13384. Epub 2018 Jun 29.
Genome-wide association studies (GWASs) have achieved great success in deciphering the genetic cause of congenital heart disease (CHD). However, the heritability of CHD remains to be clarified, and numerous genetic factors responsible for occurrence of CHD are yet unclear. In this study, we performed a genome-wide search for relaxed forms of compound heterozygosity (CH) in association with CHD using our existing GWAS data including 2265 individuals (957 CHD cases and 1308 controls). CollapsABEL was used to iteratively test the association between the CH genotype and the CHD phenotype in a sliding window manner. We highlighted 17 genetic loci showing suggestive CH-like associations with CHD (P < 5 × 10 ), among which 4 genetic loci had expression quantitative trait loci (eQTL) effects in blood (P < 0.01). After conditional association analysis, each loci had only 1 independently effective signal reaching the significance threshold (rs2071477/rs3129299 at 6p21.32, P = 2.47 × 10 ; rs10773097/rs2880921 at 12q24.31, P = 3.30 × 10 ; rs73032040/rs7259476 at 19q13.11, P = 1.14 × 10 ; rs10416386/rs4239517 at 19q13.31, P = 1.15 × 10 ), together explained 7.83% of the CHD variance. Among these 4 associated loci, outstanding candidates for CHD-associated genes included UBC, CFM2, ZNF302, LYPD3 and CADM4. Although replication studies with larger sample size are warranted, the first CH GWAS of CHD may extend our current knowledge of the genetic contributions to CHD in the Han Chinese population.
全基因组关联研究（GWAS）在解析先天性心脏病（CHD）的遗传原因方面取得了巨大成功。然而，CHD 的遗传率仍需阐明，并且许多导致 CHD 发生的遗传因素尚不清楚。在这项研究中，我们使用现有的 GWAS 数据（包括 2265 个人，957 例 CHD 病例和 1308 例对照）进行了全基因组搜索，以寻找与 CHD 相关的松弛型复合杂合子（CH）形式。我们使用 CollapsABEL 以滑动窗口的方式迭代测试 CH 基因型与 CHD 表型之间的关联。我们强调了 17 个遗传位点，这些位点与 CHD 具有提示性的 CH 样关联（P < 5×10-8），其中 4 个遗传位点在血液中具有表达数量性状基因座（eQTL）效应（P < 0.01）。在条件关联分析后，每个位点只有 1 个独立有效的信号达到显著阈值（rs2071477/rs3129299 在 6p21.32 处，P = 2.47×10-8；rs10773097/rs2880921 在 12q24.31 处，P = 3.30×10-8；rs73032040/rs7259476 在 19q13.11 处，P = 1.14×10-7；rs10416386/rs4239517 在 19q13.31 处，P = 1.15×10-7），共同解释了 CHD 变异的 7.83%。在这 4 个相关的位点中，CHD 相关基因的突出候选基因包括 UBC、CFM2、ZNF302、LYPD3 和 CADM4。尽管需要更大样本量的复制研究，但 CHD 的首次 CH GWAS 可能会扩展我们对汉族人群中 CHD 遗传贡献的现有认识。
