Association of CNVs with methylation variation

Xinghua Shi; Saranya Radhakrishnan; Jia Wen; Jin Yun Chen; Junjie Chen; Brianna Ashlyn Lam; Ryan E Mills; Barbara E Stranger; Charles Lee; Sunita R Setlur

doi:10.1038/s41525-020-00145-w

Association of CNVs with methylation variation

NPJ Genom Med. 2020 Sep 24:5:41. doi: 10.1038/s41525-020-00145-w. eCollection 2020.

Authors

Xinghua Shi^{1

2}, Saranya Radhakrishnan³, Jia Wen¹, Jin Yun Chen³, Junjie Chen^{1

2}, Brianna Ashlyn Lam¹, Ryan E Mills⁴, Barbara E Stranger⁵, Charles Lee^{6

7

8}, Sunita R Setlur³

Affiliations

¹ Department of Bioinformatics and Genomics, College of Computing and Informatics, University of North Carolina, Charlotte, North Carolina 28223 USA.
² Present Address: Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122 USA.
³ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 USA.
⁴ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109 USA.
⁵ Department of Pharmacology, Northwestern University, Chicago, Illinois 60611 USA.
⁶ The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032 USA.
⁷ Department of Life Sciences, Ewha Womans University, Seoul, 03760 South Korea.
⁸ Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061 Shaanxi China.

Abstract

Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with gene expression. CNV-mQTLs were enriched for regulatory regions, transcription factor-binding sites (TFBSs), and were involved in long-range physical interactions with associated CpGs. Some CNV-mQTLs were associated with methylation of imprinted genes. Several CNV-mQTLs and/or associated genes were among those previously reported by genome-wide association studies (GWASs). We demonstrate that germline CNVs in the genome are associated with CpG methylation. Our findings suggest that structural variation together with methylation may affect cellular phenotype.

Keywords: DNA methylation; Genetic variation.

Abstract

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