Agopian A J, Mitchell Laura E, Glessner Joseph, Bhalla Angela D, Sewda Anshuman, Hakonarson Hakon, Goldmuntz Elizabeth
Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, United States of America.
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2014 May 6;9(5):e96057. doi: 10.1371/journal.pone.0096057. eCollection 2014.
Conotruncal and related heart defects (CTDs) are a group of serious and relatively common birth defects. Although both maternal and inherited genotypes are thought to play a role in the etiology of CTDs, few specific genetic risk factors have been identified. To determine whether common variants acting through the genotype of the mother (e.g. via an in utero effect) or the case are associated with CTDs, we conducted a genome-wide association study of 750 CTD case-parent triads, with follow-up analyses in 358 independent triads. Log-linear analyses were used to assess the association of CTDs with the genotypes of both the mother and case. No association achieved genomewide significance in either the discovery or combined (discovery+follow-up) samples. However, three loci with p-values suggestive of association (p<10-5) in the discovery sample had p-values <0.05 in the follow-up sample and p-values in the combined data that were lower than in the discovery sample. These included suggestive association with an inherited intergenic variant at 20p12.3 (rs6140038, combined p = 1.0 × 10(-5)) and an inherited intronic variant in KCNJ4 at 22q13.1 (rs2267386, combined p = 9.8 × 10(-6)), as well as with a maternal variant in SLC22A24 at 11q12.3 (rs11231379, combined p = 4.2 × 10(-6)). These observations suggest novel candidate loci for CTDs, including loci that appear to be associated with the risk of CTDs via the maternal genotype, but further studies are needed to confirm these associations.
圆锥干及其相关心脏缺陷（CTDs）是一组严重且相对常见的出生缺陷。尽管母体基因型和遗传基因型都被认为在CTDs的病因中起作用，但很少有特定的遗传风险因素被确定。为了确定通过母亲基因型起作用的常见变异（例如通过子宫内效应）或病例是否与CTDs相关，我们对750个CTD病例-父母三联体进行了全基因组关联研究，并在358个独立三联体中进行了后续分析。采用对数线性分析来评估CTDs与母亲和病例基因型的关联。在发现样本或合并样本（发现样本+后续样本）中，均未发现达到全基因组显著性的关联。然而，在发现样本中p值提示有相关性（p<10-5）的三个位点，在后续样本中的p值<0.05，且合并数据中的p值低于发现样本中的p值。这些包括与20p12.3处的一个遗传性基因间变异（rs6140038，合并p = 1.0×10(-5)）、22q13.1处KCNJ4中的一个遗传性内含子变异（rs2267386，合并p = 9.8×10(-6)）以及11q12.3处SLC22A24中的一个母体变异（rs11231379，合并p = 4.2×10(-6)）存在提示性关联。这些观察结果提示了CTDs的新候选位点，包括似乎通过母体基因型与CTDs风险相关的位点，但需要进一步研究来证实这些关联。
