Abstract
Some single nucleotide polymorphisms (SNPs) influence the existence of CpG sites, the basis of DNA modification such as methylation and hydroxymethylation. These polymorphisms can lead to gain or loss of CpG sites and were defined as CpG site related SNPs (cgSNPs) in this study. The cgSNPs change DNA sequence and might potentially affect DNA modification such as methylation. However, the functional consequence of cgSNPs is poorly understood. We observed that a considerable proportion (23.0%) of common variants were cgSNPs in human genome. Mutations involving loss of CpG sites were associated with reduced levels of methylation (~20.2%) using The Cancer Genome Atlas (TCGA) data. Using public databases (SCAN and seeQTL) of expression quantitative trait loci (eQTLs), we found that the cgSNPs were significantly enriched in eQTLs via logistic regression and simulation test. Furthermore, we observed that cgSNPs were more likely to be trait-associated loci especially cancers using a catalog of published genome-wide association studies (GWAS) recorded by National Human Genome Research Institute (NHGRI). Our results indicated that cgSNP might be meaningful as annotation either in SNP functional prediction or in screening for trait-associated SNPs.
Highlights
Individual genetic variants contribute to phenotypic variants and disease susceptibility
There were 42 scenarios of single base substitution that could cause gain or loss of a CpG site (Supplementary Table 1). 80.7% of CpG site related SNPs (cgSNPs) were attributable to A/G or C/T substitutions in eight trinucleotides including CRT, CRG, CRC, CRA, AYG, CYG, GYG and TYG (R and Y were the International Union of Pure and Applied Chemistry (IUPAC) code which refers to A or G and C or T respectively).The proportions of cgSNPs among all the variants varied in different chromosomes ranging from 20.9% to 27.9%. 365098 and 9008 Single nucleotide polymorphisms (SNPs) were found to be cgSNPs located in genebodies and promoters respectively
We observed that cg-loss-SNPs accounted for a major proportion (69.0%) of cgSNPs located in CpG islands (Table 1)
Summary
Individual genetic variants contribute to phenotypic variants and disease susceptibility. Some SNPs that influence CpG dinucleotides, which can generate or abolish a CpG site. A C-to-T transition on ‘C’ of CpG dinucleotides leads to a loss of a CpG site. We defined these variants as CpG site related SNPs (cgSNPs). [1, 2] DNA methylation has been linked to transcriptional regulations [3]. Methylated regions (DMRs) have been focused by numerous studies in complex diseases. The role of DNA methylation in cancer etiology and progression is well established [4, 5]
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