Mitchell Laura E, Agopian A J, Bhalla Angela, Glessner Joseph T, Kim Cecilia E, Swartz Michael D, Hakonarson Hakon, Goldmuntz Elizabeth
Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX 77030, USA
Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX 77030, USA.
Hum Mol Genet. 2015 Jan 1;24(1):265-73. doi: 10.1093/hmg/ddu420. Epub 2014 Aug 18.
Congenital left-sided lesions (LSLs) are serious, heritable malformations of the heart. However, little is known about the genetic causes of LSLs. This study was undertaken to identify common variants acting through the genotype of the affected individual (i.e. case) or the mother (e.g. via an in utero effect) that influence the risk of LSLs. A genome-wide association study (GWAS) was performed using data from 377 LSL case-parent triads, with follow-up studies in an independent sample of 224 triads and analysis of the combined data. Associations with both the case and maternal genotypes were assessed using log-linear analyses under an additive model. An association between LSLs and the case genotype for one intergenic SNP on chromosome 16 achieved genome-wide significance in the combined data (rs8061121, combined P = 4.0 × 10(-9); relative risk to heterozygote: 2.6, 95% CI: 1.9-3.7). In the combined data, there was also suggestive evidence of association between LSLs and the case genotype for a variant in the synaptoporin gene (rs1975649, combined P = 3.4 × 10(-7); relative risk to heterozygote: 1.6, 95% CI: 1.4-2.0) and between LSLs and the maternal genotype for an intergenic SNP on chromosome 10 (rs11008222, combined P = 6.3 × 10(-7); relative risk to heterozygote: 1.6, 95% CI: 1.4-2.0). This is the first GWAS of LSLs to evaluate associations with both the case and maternal genotypes. The results of this study identify three candidate LSL susceptibility loci, including one that appears to be associated with the risk of LSLs via the maternal genotype.
先天性左侧病变（LSLs）是严重的遗传性心脏畸形。然而，关于LSLs的遗传病因知之甚少。本研究旨在确定通过受影响个体（即病例）或母亲的基因型（例如通过子宫内效应）起作用的常见变异，这些变异会影响LSLs的风险。使用来自377个LSL病例-父母三联体的数据进行了全基因组关联研究（GWAS），并在一个独立的224个三联体样本中进行了后续研究，并对合并数据进行了分析。在加性模型下，使用对数线性分析评估与病例和母亲基因型的关联。在合并数据中，16号染色体上一个基因间单核苷酸多态性（SNP）与LSLs的病例基因型之间的关联达到全基因组显著性水平（rs8061121，合并P = 4.0 × 10⁻⁹；杂合子的相对风险：2.6，95%置信区间：1.9 - 3.7）。在合并数据中，也有提示性证据表明，突触孔蛋白基因中的一个变异与LSLs的病例基因型相关（rs1975649，合并P = 3.4 × 10⁻⁷；杂合子的相对风险：1.6，95%置信区间：1.4 - 2.0），以及10号染色体上一个基因间SNP与LSLs的母亲基因型相关（rs11008222，合并P = 6.3 × 10⁻⁷；杂合子的相对风险：1.6，95%置信区间：1.4 - 2.0）。这是首次评估与病例和母亲基因型关联的LSLs全基因组关联研究。本研究结果确定了三个LSLs候选易感位点，其中一个似乎通过母亲基因型与LSLs风险相关。
