Hanchard Neil A, Swaminathan Shanker, Bucasas Kristine, Furthner Dieter, Fernbach Susan, Azamian Mahshid S, Wang Xueqing, Lewin Mark, Towbin Jeffrey A, D'Alessandro Lisa C A, Morris Shaine A, Dreyer William, Denfield Susan, Ayres Nancy A, Franklin Wayne J, Justino Henri, Lantin-Hermoso M Regina, Ocampo Elena C, Santos Alexia B, Parekh Dhaval, Moodie Douglas, Jeewa Aamir, Lawrence Emily, Allen Hugh D, Penny Daniel J, Fraser Charles D, Lupski James R, Popoola Mojisola, Wadhwa Lalita, Brook J David, Bu'Lock Frances A, Bhattacharya Shoumo, Lalani Seema R, Zender Gloria A, Fitzgerald-Butt Sara M, Bowman Jessica, Corsmeier Don, White Peter, Lecerf Kelsey, Zapata Gladys, Hernandez Patricia, Goodship Judith A, Garg Vidu, Keavney Bernard D, Leal Suzanne M, Cordell Heather J, Belmont John W, McBride Kim L
Department of Molecular and Human Genetics, Department of Pediatrics.
Department of Molecular and Human Genetics, Center for Statistical Genetics.
Hum Mol Genet. 2016 Jun 1;25(11):2331-2341. doi: 10.1093/hmg/ddw071. Epub 2016 Mar 9.
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 × 10 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 × 10, 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 × 10, 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 × 10 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 × 10 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 ([Formula: see text] 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.
涉及左侧病变（LSLs）的先天性心脏缺陷是相对常见的出生缺陷，具有较高的发病率和死亡率。先前的研究表明其遗传度较高，遗传结构复杂，因此仅鉴定出少数LSL基因座。我们进行了一项全基因组病例对照关联研究，以使用778例病例和2756例对照的发现队列来探讨常见变异的作用。我们鉴定出一个全基因组显著关联，定位于20号染色体20q11上的一个200 kb区域[rs3746446的P = 1.72 × 10 ；推断单核苷酸多态性（SNP）rs6088703的P = 3.01 × 10 ，两者的优势比（OR）= 1.6]。使用541个病例家庭的子集进行的传递不平衡分析支持了这一结果（该区域最低P = 4.51 × 10 ，OR = 1.5）。在367例LSL病例和5159例对照的队列中进行的重复验证显示出名义上的关联（rs3746446的P = 0.03），对合并队列进行荟萃分析后，rs3746446的P = 9.49 × 10 。此外，1号染色体1q21.3上的一组7个SNP达到了提示性关联的阈值（rs12045807的最低P = 9.35 × 10 ）。这两个区域都包含参与心脏发育的基因——20号染色体上的MYH7B/miR499A以及1号染色体上的CTSK、CTSS和ARNT。使用病例对照基因分型SNP进行的全基因组遗传度分析表明，归因于常见变异的LSLs的平均遗传度中等偏高（[公式：见正文]范围 = 0.26 - 0.34），与先前的断言一致。这些结果为常见变异在LSLs中的作用提供了证据，提出了新的基因作为潜在的生物学候选基因，并进一步深入了解了先天性心脏病的复杂遗传结构。
