Three of the top variant sets involved the dopamine transporter gene, SLC6A3, also known as DAT1, which has been extensively studied for association with AD because of dopamine’s role in reward processes. Most previous genetic studies have focused on the 40-base-pair variable-number tandem repeat (VNTR) in the 3′-unstranslated region (3′-UTR) of the gene. There has been mixed evidence for association of genetic variants in this region with AD(Du et al., 2011), although a recent meta-analysis found a significant association with the A9 genotype(Ma et al., 2016). Our variant set findings implicate the opposite end of this gene, specifically the promoter region, suggesting that genetic variants in this region of the gene may influence AD by regulating gene expression. Bioinformatic analyses of SLC6A3 have shown an abundance of CpGs in the promoter implicating DNA methylation as the regulatory mechanism (Shumay et al., 2010). DNA methylation (Kerkel et al., 2008) has been shown to be regulated by genetic variation and there is ample evidence suggesting that this in turn may affect gene regulation/expression. In the specific context of addiction, a recent study showed that different genotypes influence epigenetic modifications and gene transcription differently in response to cocaine (Vasiliou et al., 2012).
