Mapping methylation quantitative trait loci in cardiac tissues nominates risk loci and biological pathways in congenital heart disease

Ming Li,Philip J Lupo,Catherine Do,Chen Lyu,Nianjun Liu,Benjamin Tycko,John S Witte,Stewart L Macleod,Charlotte A Hobbs,Christopher E Randolph,Manyan Huang

doi:10.1186/s12863-021-00975-2

Abstract

BackgroundMost 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.ResultsWe 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.ConclusionsOur 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.

Highlights

Most congenital heart defects (CHDs) result from complex interactions among genetic susceptibilities, epigenetic modifications, and maternal environmental exposures
We showed that a few genomic regions may potentially harbor genetic variants that simultaneously influence DNA methylation, gene expression, or CHD risk
Our results can serve as an important source of information that can be integrated with other genetic studies of heart diseases, especially CHDs

Summary

Introduction

Most congenital heart defects (CHDs) result from complex interactions among genetic susceptibilities, epigenetic modifications, and maternal environmental exposures. 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. Epigenetic modifications, such as DNA methylation, arise in response to internal and external stimuli and lead to metastable alterations of gene expression during cell development and proliferation, facilitating the adaptation of an individual cell to its environment [1]. By this reasoning, mapping of mQTLs in disease-relevant human tissues, followed by overlapping such maps with genome wide association study (GWAS) data, can point to functional regulatory SNPs (rSNPs) that can affect disease risk [13, 14]

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