For example, we consistently identified strong associations between POU and poor metabolic function (e.g., increased triglyceride levels, lower HDL cholesterol, high blood glucose levels), which can result in serious downstream health consequences. These results are consistent with previous studies showing poor metabolic function in individuals who misuse opioids [59], and in morphine-induced rats [60]. Some metabolic markers, such as calcium and folate, have been previously associated with opioid misuse [61, 62], whereas others (calcitriol) were identified as novel. Although it has been previously speculated that reduced metabolic biomarkers (calcium, folate) in high opioid users could be a direct consequence of repeated exposure to opioids, our results suggest that at least part of the previously reported correlations are due to common genetic factors that influence opiate use, calcium and folate. POU PRS was also associated with blood-related biomarkers, including increased erythrocyte and decreased lymphocyte counts, consistent with previous phenotypic studies [63, 64]. We observed an association between POU PRS and decreased carbon dioxide and creatinine levels, contrary to a previous finding showing that opioids can decrease sensitivity of peripheral chemoreceptors in
