ABSTRACTNumerous DNA methylation (DNAm) biomarkers of cigarette smoking have been identified in peripheral blood studies, but their relevance as neurobiological indicators is unknown due to DNAm tissue-specificity. In contrast, blood-based studies may not detect brain-specific smoking-related DNAm differences that may provide greater insight into the neurobiology of smoking behaviors. We report the first epigenome-wide association study (EWAS) of smoking in human postmortem brain, focusing on nucleus accumbens (NAc) as a key brain region in developing addiction. Following Illumina HumanMethylation EPIC array data generation and quality control, 221 decedents (120 European American [23% current smokers], 101 African American [26% current smokers]) were analyzed. DNAm by smoking (current vs. nonsmoking) was tested using robust linear regression models adjusted for age, sex, cell-type proportion, DNAm-derived negative control principal components (PCs), and genotype-derived PCs. Separate ancestry-specific results were combined via meta-analysis, resulting in 7 CpGs that exceeded false discovery rate (FDR)<0.05. Using published smoking EWAS results in blood, we extended our NAc findings to identify DNAm smoking effects that are unique (tissue-specific) versus shared between tissues (tissue-shared). Of the 7 CpGs identified in NAc, 3 CpGs were located near genes previously indicated with blood-based smoking DNAm biomarkers: ZIC1, ZCCHC24, and PRKDC. The other 4 CpGs are novel for smoking-related DNAm changes: ABLIM3, APCDD1L, MTMR6, and CTCF. Our results provide the first evidence for smoking-related DNAm changes in human NAc, highlighting CpGs that were previously undetected as peripheral biomarkers and may reflect brain-specific processes.
Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers