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

Markunas, C. A.; Semick, S. A.; Quach, B. C.; Tao, R.; Deep-Soboslay, A.; Bierut, L. J.; Hyde, T. M.; Kleinman, J. E.; Johnson, E. O.; Jaffe, A. E.; Hancock, D. B.

doi:10.1101/781542

bioRxiv · 10.1101/781542

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

Markunas, C. A.·Semick, S. A.·Quach, B. C.·Tao, R.·Deep-Soboslay, A.·Bierut, L. J.·Hyde, T. M.·Kleinman, J. E.·Johnson, E. O.·Jaffe, A. E.·Hancock, D. B.

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Abstract

Numerous 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.

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Markunas, C. A., Semick, S. A., Quach, B. C., Tao, R., Deep-Soboslay, A., Bierut, L. J., Hyde, T. M., Kleinman, J. E., Johnson, E. O., Jaffe, A. E., Hancock, D. B.. 2019-09-25. Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers. https://doi.org/10.1101/781542

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