TY - JOUR
T1 - Association of CNVs with methylation variation
AU - Shi, Xinghua
AU - Radhakrishnan, Saranya
AU - Wen, Jia
AU - Chen, Jin Yun
AU - Chen, Junjie
AU - Lam, Brianna Ashlyn
AU - Mills, Ryan E.
AU - Stranger, Barbara E.
AU - Lee, Charles
AU - Setlur, Sunita R.
N1 - Funding Information:
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.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41525-020-00145-w
DO - 10.1038/s41525-020-00145-w
M3 - Article
C2 - 33062306
AN - SCOPUS:85091404006
VL - 5
JO - npj Genomic Medicine
JF - npj Genomic Medicine
SN - 2056-7944
IS - 1
M1 - 41
ER -