Abstract:DNA methylation (DNAm) has been linked to changes in chromatin structure, gene expression and disease. The DNAm level can be affected by genetic variation; although, how this differs by CpG dinucleotide density and genic location of the DNAm site is not well understood. Moreover, the effect of disease causing variants on the DNAm level in a tissue relevant to disease has yet to be fully elucidated. To this end, we investigated the phenotypic profiles, genetic effects and regional genomic heritability for 19608… Show more
“…Therefore, our results suggest that popDNAm in colon is driven by population specific genetic variation in cis . Overall, these results are consistent with the observation of significant cis heritability for DNAm sites in populations of pure ancestry (5,6). Figure 1.Summary of popDNAm sites across both tissues considered.…”
Section: Population-specific Dnam In Normal Colon Tissuesupporting
confidence: 89%
“…In general, variation of DNAm within a population has been demonstrated to have both significant genetic components (5,6) as well as strong associations with environmental factors (7,8). In admixed individuals, cis ancestral genetic context differs across DNAm sites.…”
DNA methylation (DNAm) measured in lymphoblastoid cell lines has been repeatedly demonstrated to differ between various human populations. Due to the role that DNAm plays in controlling gene expression, these differences could significantly contribute to ethnic phenotypic differences. However, because previous studies have compared distinct ethnic groups where genetic and environmental context are confounded, their relative contribution to phenotypic differences between ethnicities remains unclear. Using DNAm assayed in whole blood and colorectal tissue of 132 admixed individuals from Colombia, we identified sites where differential DNAm levels were associated with the local ancestral genetic context. Our results are consistent with population specific DNAm being primarily driven by between population genetic differences in cis, with little environmental contribution, and with consistent effects across tissues. The findings offer new insights into a possible mechanism driving phenotypic differences among different ethnic groups, and could help explain ethnic differences in colorectal cancer incidence.
“…Therefore, our results suggest that popDNAm in colon is driven by population specific genetic variation in cis . Overall, these results are consistent with the observation of significant cis heritability for DNAm sites in populations of pure ancestry (5,6). Figure 1.Summary of popDNAm sites across both tissues considered.…”
Section: Population-specific Dnam In Normal Colon Tissuesupporting
confidence: 89%
“…In general, variation of DNAm within a population has been demonstrated to have both significant genetic components (5,6) as well as strong associations with environmental factors (7,8). In admixed individuals, cis ancestral genetic context differs across DNAm sites.…”
DNA methylation (DNAm) measured in lymphoblastoid cell lines has been repeatedly demonstrated to differ between various human populations. Due to the role that DNAm plays in controlling gene expression, these differences could significantly contribute to ethnic phenotypic differences. However, because previous studies have compared distinct ethnic groups where genetic and environmental context are confounded, their relative contribution to phenotypic differences between ethnicities remains unclear. Using DNAm assayed in whole blood and colorectal tissue of 132 admixed individuals from Colombia, we identified sites where differential DNAm levels were associated with the local ancestral genetic context. Our results are consistent with population specific DNAm being primarily driven by between population genetic differences in cis, with little environmental contribution, and with consistent effects across tissues. The findings offer new insights into a possible mechanism driving phenotypic differences among different ethnic groups, and could help explain ethnic differences in colorectal cancer incidence.
“…Damage to DNA from ROS is a consequence of oxidative stress and several oxidative DNA adducts, including 8-oxodG, have been implicated in the tumorigenic process (Aranganathan and Nalini, 2009). To induce colorectal tumors, the potency of DMH is the reason of inducing DNA methylation (Rowlatt et al, 2016), which was strongly associated with abnormal gene expression and tumorgenesis (Salehi et al, 2015).…”
The present study was designed to investigate the ameliorative effect of vitamin C administration on serum alanine aminotransferase (ALT),aspartate aminotransferase(AST),Urea, Creatinine, Alphafetoprotein(AFP), Carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA 19-9), in addition to tumor necrosis factor alpha (TNF-α) , Cytochromep4502E1 and Caspase-9 gene expression in colon cancer induced by 1,2-dimethylhydrazine (DMH)in rats. Forty white female albino rats were divided into four equal groups (10 each). Group I(control group):received no drugs. Group II:(DMH group): rats injected subcutaneously with DMH (35 mg/kg body weight),twice a week for 5 consecutive weeks for colon cancer induction. Group III:(protective group): rats administrated vit C(200 mg kg-1 b. wt) orally and for 4 weeks before DMH injection and continued with vit C administration daily till the end of the experiment .Group IV:(treatment group):rats injected subcutaneously with DMH then administrated Vit C for 6 weeks till the end of the experiment. Blood and colon tissue samples were collected from all animal groups at the end of the experiment. The obtained results showed that DMH injection to rats significantly increased serum(ALT, AST, Urea, Creatinine, AFP, CEA, CA 19-9) and colon tissue TNF-α and CYP2E1while colon tissue caspase-9 gene wassignificantly decreasedwhen compared to control.Administration of Vit C significantly decreased serum (ALT, AST, Urea, Creatinine, AFP, CEA, CA 19-9) in addition to TNF-α and CYP2E1in colon tissue. How every, caspase-9 gene expression showed a significant increase. Histopathological examination of colon tissue edesquamation of the colon epithelium with heavy leukocytic infiltrationin DMH group. While administration of vitamin C in colon cancer induced rats showed mild destruction of the lining epithelium with mild leukocytic infiltration in addition to mild malignancy of epithelium when compared to DMH group. These results indicated the protective effect of Vit C against DMH induced colon cancer.
“…A family study showed an average heritability of 13% in CD4 + cells (3). One study reported an average SNP-heritability of 29% across heritable CpG sites in colorectum (51). There has been to date only one study that estimated the SNP-heritability of DNAm in brain, but that was limited to ~27,000 CpGs located primarily in promoters (8).…”
DNA methylation (DNAm) is heritable and plays a role in brain development and function through transcriptional regulation. Aberrant DNAm in human brain has been linked to psychiatric disorders, potentially as mediators of common genetic risk variants. In this study, we hypothesize that common risk variants for psychiatric disorders may act through affecting DNAm level in human brain. We first aimed to investigate the heritability pattern of DNAm levels in the human prefrontal cortex. Secondly, through imputation-driven methylome-wide association study (MWAS), we aimed to identify CpG sites whose methylation levels are genetically associated and that show methylation-trait associations in the prefrontal cortex of patients with schizophrenia or bipolar disorder. Our heritability analysis showed that, of ~370,000 CpG sites measured with the Illumina HumanMethylation450 microarray, 17% were heritable (p < 0.05), with a mean heritability of 0.22. Heritable CpG sites were enriched in intergenic regions, CpG shore, and regulatory regions in prefrontal cortex. Our MWAS approach identified known and potentially novel risk genes harboring CpG sites of methylation-trait associations for schizophrenia or bipolar disorder, which were not detectable using three alternative strategies (blood-based methylome reference, transcriptome-wide association study, and two gene-based association tests). Gene set enrichment analysis for genes with methylation-trait association evidence revealed pathways clearly related to neuronal functions, but also highlighted additional biological mechanisms that may underlie psychiatric disorders, such as microRNA-related regulation. In conclusion, our results showed the power of integrating brain methylation data with GWAS for psychiatric risk gene discovery, with potential applications in brain-related disorders or traits. peripheral tissue (blood), which may not correlate with methylation signals in the brain (18, 19).Additionally, due to the challenges of accessing brain tissues, studies that examined brain samples were often limited by small sample size. Finally, it is hard to establish a causal role between DNAm change and disease as it is unclear whether aberrant DNAm causes disease or vice versa.Genome-wide association studies (GWAS) indicate that most common genetic risk variants underlying complex diseases are noncoding and enriched in regulatory genomic regions in cells or tissues related to disease (20), suggesting that risk variants may act through regulation of cell/tissue-specific molecular mechanisms, such as methylation or gene expression. For example, SCZ risk variants from GWAS were enriched at enhancers active in brain, but not in tissues unlikely to be relevant to SCZ (21). Furthermore, statistical genetic approaches like linkage disequilibrium (LD) score regression have shown enrichment of trait heritability in regions with functional annotations that are trait-related and cell-type-specific, including enrichment of heritability for SCZ and BP in functional regions specific to th...
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