Mapping methylation quantitative trait loci in cardiac tissues nominates risk loci and biological pathways in congenital heart disease.
Mapping methylation quantitative trait loci in cardiac tissues nominates risk loci and biological pathways in congenital heart disease.
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DOI：
10.1186/s12863-021-00975-2
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发表时间：
2021-06-10
期刊：
影响因子：
1.9
通讯作者：
Hobbs CA
中科院分区：
文献类型：
--
作者：
Li M;Lyu C;Huang M;Do C;Tycko B;Lupo PJ;MacLeod SL;Randolph CE;Liu N;Witte JS;Hobbs CA
大多数先天性心脏病(CHD)是遗传易感性、表观遗传修饰和母体环境暴露之间复杂的相互作用的结果。表征遗传、表观遗传和转录变异之间的复杂关系将增强我们对这种重要类型先天性疾病的发病机制的理解。我们在83个心脏组织样本中研究了遗传单核苷酸多态(SNPs)对局部DNA甲基化模式的顺式作用效应，并通过利用CHD全基因组关联研究(GWAS)的结果及其对心脏基因表达的影响来优先考虑它们对CHD风险的贡献。我们识别了13,901个潜在的甲基化数量性状基因座(MQTL)，错误发现阈值为5%。进一步的共定位分析和孟德尔随机化研究表明，6号染色体上HLADRB6基因附近的遗传变异可能通过调节附近CpG位点的甲基化状态而导致CHD风险。位于10号染色体(TNKS2-AS1基因)和14号染色体(LINC01629基因)基因组区域的额外SNP可能同时影响心脏组织的表观遗传和转录变异。我们的结果支持这样的假设，即遗传变异可能通过调节DNA甲基化和基因表达的变化来影响CHD的风险。我们的结果可以作为一个重要的信息来源，可以与其他心脏病，特别是先天性心脏病的遗传学研究相结合。网上版载有补充材料，可在10.1186/s12863-021-00975-2查阅。
Most congenital heart defects (CHDs) result from complex interactions among genetic susceptibilities, epigenetic modifications, and maternal environmental exposures. Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation will enhance our understanding of pathogenesis in this important type of congenital disorder. We investigated cis-acting effects of genetic single nucleotide polymorphisms (SNPs) on local DNA methylation patterns within 83 cardiac tissue samples and prioritized their contributions to CHD risk by leveraging results of CHD genome-wide association studies (GWAS) and their effects on cardiac gene expression. We identified 13,901 potential methylation quantitative trait loci (mQTLs) with a false discovery threshold of 5%. Further co-localization analyses and Mendelian randomization indicated that genetic variants near the HLA-DRB6 gene on chromosome 6 may contribute to CHD risk by regulating the methylation status of nearby CpG sites. Additional SNPs in genomic regions on chromosome 10 (TNKS2-AS1 gene) and chromosome 14 (LINC01629 gene) may simultaneously influence epigenetic and transcriptomic variations within cardiac tissues. Our results support the hypothesis that genetic variants may influence the risk of CHDs through regulating the changes of DNA methylation and gene expression. Our results can serve as an important source of information that can be integrated with other genetic studies of heart diseases, especially CHDs. The online version contains supplementary material available at 10.1186/s12863-021-00975-2.
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影响因子：
2.1
作者：
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通讯作者：
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