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Opioid Dependence Linked to Decreased Methylation in Several Genes

NEW YORK (GenomeWeb) – A team led by researchers at Yale University has found a handful of cytosine marks with lower-than-usual methylation levels in an epigenome-wide association study (EWAS) of European-American women with opioid dependence.

The researchers performed array-based methylation profiling on blood samples from 220 women, including 140 individuals with opioid dependence and 80 opioid-exposed controls, recruited through the Yale University School of Medicine or the University of Connecticut Health Center. The data showed three opioid dependence-associated CpG sites around the PARG, RERE, and CFAP77 genes, which are involved in processes ranging from chromatin remodeling and DNA binding to cell survival and cell projection.

"Our findings implicate epigenetic mechanisms in [opioid dependence] and, if replicated, identify possible novel peripheral biomarkers of [opioid dependence] that could inform the prevention and treatment of the disorder," senior and corresponding author Joel Gelernter, a researcher at Yale, and his colleagues wrote in their study, published online today in Scientific Reports.

Past studies suggest that blood DNA methylation may rise, in general, in individuals with opioid dependence, the team noted, though prior epigenetic analyses on blood and other samples from individuals with opioid dependence have been limited and have not produced consistent results.

The researchers focused their EWAS on women, who appear to be more prone to using opioids or other prescription drugs. They noted that while higher rates of opioid dependence have been documented in men, there has also been a significant rise in opioid relapses and overdoses in women.

To search for epigenetic contributors to this process, they used Illumina Infinium Human MethylationEPIC BeadChip arrays to profile more than 800,000 cytosine methylation sites in the genome in whole blood samples from 140 American women of European descent with opioid dependence and 80 European-American women exposed to opioids at least 10 times who had not developed dependence.

By comparing cases and controls, the team saw genome-wide significant methylation associations at three CpG sites in the women with opioid dependence: declines in methylation at cg17426237 in the chromosome 10 gene PARG, at cg21381136 near the chromosome 1 gene RERE, and at the chromosome 9 site cg18177613 in the CFAP77 gene.

The authors cautioned that the individuals with opioid dependence also had more alcohol or cocaine dependence than the control individuals. Even so, the methylation associations they detected in the EWAS held up after adjusting for participants' age, cell proportion estimates, and other potential confounders.

On the other hand, the investigators did not detect significant differences in blood-based methylation marks used to estimate biological age when comparing the two groups of women.

From there, the team looked for potential overlap between methylation quantitative trait locus SNPs and sites with altered methylation in the opioid dependence cases — an analysis that pointed to a potential, nominal association between decreased methylation at the cg17426237 site and a variant in the PRKG1 gene.

The same PRKG1 SNP showed tenuous ties to opioid dependence in a prior genome-wide association study, the researchers reported, while variants in the RERE gene have been implicated in psychiatric conditions such as schizophrenia, bipolar disorder, and autism spectrum disorder in past GWAS.

These and other findings "support the interpretation that DNA methylation differences could be attributable to both environmental and genetic influences," the authors wrote, suggesting that risk variants linked to opioid dependence "could reflect epigenetic regulatory loops, modulating gene expression by an epigenetic mechanism."