The novelty of our approach using human iN cells to investigate the synaptic impact of a major functional OPRM1 SNP is that these cells carry the genetic signatures of the subjects from whom they were derived. Identifying identical DAMGO-mediated responses across multiple subject-derived and CRISPR-edited cell lines generated using independently executed targeting strategies clearly demonstrates that the observed effect is a direct consequence of only the MOR N40D variant. In fact, the use of human stem cell derived neurons provides novel information about human specific mechanisms of a highly prevalent OPRM1 SNP, A118G, in response to opioids 36. Thus, we show the utility of disease modeling using stem cell derived disease-relevant cell types as a framework to the field of addiction for conducting future mechanistic analyses.
