Our study has limitations that must be noted. Although the sample size was large in comparison with other published population genetics studies of OD, when one sets out to study RVs, unconventionally-large samples may be required to identify associations with particular variants – because they are, definitional, rare. Thus, statistical techniques such as binning must be relied upon. While we feel the support for association presented in this article is compelling, there is wide latitude for disagreement on this point, and little that can be done to address this statistically practically, until larger samples of OD subjects become widely available. Also, this study was by nature a candidate gene study focused on particular pathways. As is always the case with pathways-based studies, selection of genes for inclusion is somewhat subjective, and more so for brain-based systems which are particularly complex. It is entirely possible, perhaps even likely, that other glutamate-system genes will in future be shown to be associated with OD and other substance dependence traits. Learning if this is true will have to await other even more extensive gene based studies, of full exome or genome sequencing studies.
