Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers

Cigarette smoking remains the leading cause of preventable death worldwide. Cigarette smoking behaviors (e.g., initiation, nicotine dependence, cessation) are heritable, and many genetic risk loci have been identified. However, the neurobiological mechanisms underlying the genetic risk loci along the trajectory of smoking are largely unknown. DNA methylation (DNAm) differences between smokers and nonsmokers can provide insight into mechanisms that predispose to smoking behaviors and consequences of the smoking exposure itself. Differential DNAm by smoking has been found at many CpG sites in blood, but because of the tissue specificity of gene regulation, differential DNAm that can only be detected in brain may have been missed. Here, we provide Illumina HumanMethylationEPIC array data generated in nucleus accumbens, an addiction-relevant brain tissue, from 221 deceased individuals: 53 current cigarette smokers, 168 nonsmokers. From these data, we have conducted an epigenome-wide association study (EWAS) and identified several CpG associations with smoking. A subset of the identified CpGs map to genes that were previously indicated as blood-based smoking DNAm biomarkers, but the other CpGs map to genes that were previously undetected in blood and may reflect brain-specific processes related to smoking. Genome-wide DNAm data were measured in postmortem nucleus accumbens tissue with the HumanMethylationEPIC BeadChip array. The dataset includes 221 deceased individuals: 101 African Americans (23% current cigarette smokers, 77% nonsmokers) and 120 European Americans (26% current cigarette smokers, 74% nonsmokers).吸烟仍是全球范围内可预防死亡的首要诱因。吸烟行为（如吸烟起始、尼古丁依赖、戒烟）具有可遗传性，目前已鉴定出多个遗传风险位点，但沿吸烟发展轨迹发挥作用的遗传风险位点背后的神经生物学机制仍未得到充分阐明。吸烟者与非吸烟者之间的DNA甲基化（DNA methylation，简称DNAm）差异，可为吸烟行为的易感机制以及吸烟暴露本身所带来的后果提供研究视角。目前已在血液的多个CpG位点（CpG site）中发现吸烟相关的DNA甲基化差异，但由于基因调控的组织特异性，仅在脑组织中可检测到的DNA甲基化差异可能被遗漏。本研究提供了来自221名已故个体的伏隔核（nucleus accumbens，一种与成瘾相关的脑组织）中的Illumina HumanMethylationEPIC芯片（Illumina HumanMethylationEPIC array）数据：其中当前吸烟者53名，非吸烟者168名。基于上述数据，本研究开展了表观全基因组关联研究（epigenome-wide association study，EWAS），并鉴定出多个与吸烟相关的CpG位点关联。其中部分鉴定出的CpG位点所在基因曾被作为血液来源的吸烟相关DNAm生物标志物，而其余CpG位点所在基因此前在血液中未被发现，可能反映了与吸烟相关的脑组织特异性生物学过程。本研究采用HumanMethylationEPIC BeadChip芯片对死后伏隔核组织进行了全基因组DNAm检测。本数据集共纳入221名已故个体，其中101名为非裔美国人（当前吸烟者占23%，非吸烟者占77%），120名为欧洲裔美国人（当前吸烟者占26%，非吸烟者占74%）。