A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20
A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20
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DOI：
10.1093/hmg/ddw071
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发表时间：
2016-06-01
影响因子：
3.5
通讯作者：
McBride, Kim L.
中科院分区：
文献类型：
--
作者：
Hanchard, Neil A.;Swaminathan, Shanker;McBride, Kim L.
先天性心脏病涉及左侧病变（LSL）是相对常见的出生缺陷与大量的发病率和死亡率。以前的研究表明，具有复杂遗传结构的高遗传力，因此只有少数LSL基因座已被确定。我们进行了一项全基因组病例对照关联研究，使用778例病例和2756例对照的发现队列来解决常见变异的作用。我们确定了染色体20 q11上200 kb区域的全基因组显著关联映射[rs3746446 P= 1.72 x 10（-8）;估算的单核苷酸多态性（SNP）rs6088703 P= 3.01 x 10（-9），比值比（OR）= 1.6]。这一结果得到了使用541个病例家庭子集进行的传播不平衡分析的支持（区域内最低P = 4.51 × 10（-5），OR= 1.5）。在367例LSL病例和5159例对照的队列中进行的重复显示出名义相关性（rs3746446的P= 0.03），在对合并队列进行荟萃分析时，rs3746446的P= 9.49 x 10（-9）。此外，染色体1q21.3上的一组7个SNP符合提示性关联的阈值（rs 12045807的最低P= 9.35 x 10（-7））。这两个区域都包括参与心脏发育的基因-20号染色体上的MYH 7 B/miR 499 A和1号染色体上的CTSK、CTSS和ARNT。使用病例对照基因型SNP的全基因组遗传力分析表明，归因于常见变异的LSL的平均遗传力中等偏高（h范围= 0.26-0.34），与先前的断言一致。这些结果为LSL中常见变异的作用提供了证据，提供了新的基因作为潜在的生物学候选基因，并进一步了解了先天性心脏病复杂的遗传结构。
Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 x 10(-8) for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 x 10(-9), odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 x 10(-5), OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 x 10(-9) for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 x 10(-7) for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high h range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.