Examining the role of mitochondrial genetic variation in nicotine dependence

•Mitochondrial genetic variation was examined in nicotine dependent subjects.•One mitochondrial DNA variant, m.1700T>C in the MT-RNR2 gene, was associated with age of onset of daily smoking.•One nuclear-encoded mitochondrial gene, PRKACA, and SNP rs78417112, in the HSD17B4 gene were associated with age of onset of first and occasional smoking.•Findings suggest mitochondrial genetic variation may contribute to variability in smoking phenotypes, although replication in larger samples is required. Nicotine dependence (ND) has a heritability rate of ∼50%, suggesting genetic factors contribute to underlying mechanisms. Here, we aimed to examine variants within both mtDNA and the nuclear genome to determine if mitochondrial genes are associated with ND. A total of 129 mtDNA SNPs and 1136 nuclear-encoded mitochondrial genes in a sample of N = 374 Caucasians were selected for analysis. Age of onset of first, occasional, and daily smoking and Fagerström Test for Nicotine Dependence were used as outcomes for the analysis. Linear regression was used to test common variants. Gene analyses were performed using MAGMA. One nuclear mitochondrial SNP, rs78417112 found in the HSD17B4 gene, was significantly associated with the age of onset of occasional smoking. Additionally, one nuclear mitochondrial gene, PRKACA, was significantly associated with age of onset of both first and occasional smoking. Replication testing of the mtDNA m.1700T>C SNP, nominally associated with age of onset of daily smoking, was available in the PNAT2 clinical trial (N = 930 Caucasians). A meta-analysis showed this SNP was associated with age of onset of daily smoking (p-value = 0.004). Overall, the findings suggest mitochondrial genetic variation may contribute to variability in smoking phenotypes, although replication in larger samples is required.