Our focus on opioid misusers is a major strength; the modest size of our OUIP groups is an unavoidable limitation. Our assumption that SNPs can offer protection against transitions at different points of the addictive process is supported by the existing animal literature.26–29 We only examined confirmation of the CNIH3 SNP associations; a broader examination might have confirmed other CATS associations. Since both the epigenetic landscape and motif analysis support its potential functionality, our neuroimaging genetics study focused on rs10799590 with post-hoc analyses confirming it as the CNIH3 SNP most strongly associated with amygdala habituation. Future work should incorporate examination of the other GWS SNPs (e.g., rs298733 also affects TF binding - Supplementary Table 6) and the possibility of more highly associated, non-genotyped polymorphisms in high LD. Although similarly ascertained samples e.g., 61 have comparable rates of daily opioid injection, reports in other populations have noted lower prevalence. e.g.,62 A more detailed characterization of the OUIP groups’ opioid use would have been useful, but was not obtained. We examined somewhat divergent ODE’s in our confirmation samples because of ascertainment and
