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

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^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

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.

Original language	English (US)
Article number	41
Journal	npj Genomic Medicine
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s41525-020-00145-w
State	Published - Dec 1 2020

Funding

We acknowledge Dr. Job Dekker on his advice on the Hi-C analysis, Dr. Towfique Raj for advice on QTL analysis, Sudeep Setlur with the ENCODE analysis, and Drs. Stephen Samson, Silvia Liu, and Qihui Zhu for their helpful review of the manuscript. This work was supported by National Institutes of Health [grant number U41HG007497 to authors C.L. and R.E.M.), NIH 1R01HG007068-01A1 (R.E.M.), NIH R15HG009565 (X.S.); National Cancer Institute (NIH-NCI) SPORE, Developmental Project Award (5P50CA090381, S.R.S.); Department of Defense (DOD) (W81XWH-15-1-0089 and W81XWH-16-1-0687 to S.R.S.), and Eleanor and Miles Shore scholarship in Medicine award and the Brigham and Women’s Hospital, Connors‐BRI Center for Research on Women’s Health and Gender Biology (S.R.S.). C.L. was a distinguished Ewha Womans University Professor, supported in part by the Ewha Womans University Research grant of 2018–2019. This study is also supported in part by the operational funds from The First Affiliated Hospital of Xi’an Jiaotong University.

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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title = "Association of CNVs with methylation variation",

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.",

author = "Xinghua Shi and Saranya Radhakrishnan and Jia Wen and Chen, {Jin Yun} and Junjie Chen and Lam, {Brianna Ashlyn} and Mills, {Ryan E.} and Stranger, {Barbara E.} and Charles Lee and Setlur, {Sunita R.}",

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Association of CNVs with methylation variation

Abstract

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