Department of Pediatrics, Columbia University Irving Medical Center, United States; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, United States.
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, United States.
Drug Alcohol Depend. 2021 Apr 1;221:108658. doi: 10.1016/j.drugalcdep.2021.108658. Epub 2021 Feb 26.
Opioid abuse poses significant risk to individuals in the United States and epigenetic changes are a leading potential biomarker of opioid abuse. Current evidence, however, is mostly limited to candidate gene analysis in whole blood. To clarify the association between opioid abuse and DNA methylation, we conducted an epigenome-wide analysis of DNA methylation in brain samples of individuals who died from acute opioid intoxication and group-matched controls.
Tissue samples were extracted from the dorsolateral prefrontal cortex of 153 deceased individuals (M = 35.42; 62 % male; 77 % European ancestry). The study included 72 opioid samples, 53 psychiatric controls, and 28 normal controls. The epigenome-wide analysis was implemented using the Illumina MethylationEPIC BeadChip; analyses adjusted for sociodemographic characteristics, negative control principal components, ancestry principal components, cellular composition, and surrogate variables. Horvath's epigenetic age and Levine's PhenoAge were calculated, and gene set enrichment analyses were performed.
Although no CpG sites survived false-discovery rate correction for multiple testing, 13 sites surpassed a relaxed significance threshold (p < 1.0 × 10). One of these sites was located within Netrin-1, a gene implicated in kappa opioid receptor activity. There was an association between opioid use and accelerated PhenoAge (b = 2.24, se = 1.11, p = .045). Gene set enrichment analyses revealed enrichment of differential methylation in GO and KEGG pathways broadly related to substance use.
Netrin-1 may be associated with opioid overdose, and future research with larger samples across stages of opioid use will elucidate the complex genomics of opioid abuse.
阿片类药物滥用给美国的个人带来了重大风险，而表观遗传变化是阿片类药物滥用的一个主要潜在生物标志物。然而，目前的证据主要局限于全血中候选基因的分析。为了阐明阿片类药物滥用与 DNA 甲基化之间的关系，我们对死于急性阿片类药物中毒的个体和匹配的对照组的大脑样本进行了全基因组 DNA 甲基化的表观基因组分析。
从 153 名已故个体的背外侧前额叶皮层中提取组织样本（M = 35.42；62%为男性；77%为欧洲血统）。该研究包括 72 个阿片类样本、53 个精神病对照组和 28 个正常对照组。使用 Illumina MethylationEPIC BeadChip 进行全基因组表观基因组分析；分析调整了社会人口特征、阴性对照主成分、祖先主成分、细胞组成和替代变量。计算了 Horvath 的表观遗传年龄和 Levine 的 PhenoAge，并进行了基因集富集分析。
尽管没有 CpG 位点通过多重检验的假发现率校正而幸存下来，但有 13 个位点超过了宽松的显著性阈值（p < 1.0 × 10）。其中一个位点位于 Netrin-1 内，该基因与κ阿片受体活性有关。阿片类药物使用与加速的 PhenoAge 之间存在关联（b = 2.24，se = 1.11，p =.045）。基因集富集分析显示，GO 和 KEGG 通路的差异甲基化富集与物质使用广泛相关。
Netrin-1 可能与阿片类药物过量有关，未来的研究将在阿片类药物使用的各个阶段使用更大的样本，阐明阿片类药物滥用的复杂基因组学。
