In summary, we report a GWS association of rs12442183, at the RGMA locus, with OD. In contrast to our earlier study, the present study includes only opioid-exposed subjects selected from an expanded sample; and our analyses for this study did not co-vary for the criterion count for other substance use disorder traits. We believe that the former two differences were key in our identification of the present very robust association finding. The finding was GWS in our largest sample taken separately, with nominally significant associations of the same variant in two of three other available samples of EAs. Further support was obtained in AA samples. Our current data support a model in which the regulatory variant rs12442183 affects expression of RGMA transcript variant 4 in frontal cortex, and the consequent variation in RGMa isoform 3 may alter the response to opioids, a potential underlying mechanism for its association with OD. This mechanism and locus merit further study, which could increase our understanding of the genetics and pathophysiology of OD.
