Unique and joint associations of polygenic risk for major depression and opioid use disorder with endogenous opioid system function.

Major depressive disorder (MDD) and opioid use disorder (OUD) are common, potentially fatal, polygenic disorders that are moderately heritable and often co-occur. We examined the unique and shared associations of polygenic risk scores (PRS) for these disorders with µ-opioid receptor (MOR) concentration and endogenous opioid response during a stressful stimulus. Participants were 144 healthy European-ancestry (EA) subjects (88 females) who underwent MOR quantification scans with [ 11 C]carfentanil and PET and provided DNA for genotyping. MOR non-displaceable binding potential (BP ND ) was measured in 5 regions of interest (ROIs) related to mood and addiction. We examined associations of PRS both at baseline and following opioid release calculated as the ratio of baseline and stress-challenge scans, first in the entire sample and then separately by sex. MOR availability at baseline was positively associated with MDD PRS in the amygdala and ventral pallidum. MDD and OUD PRS were significantly associated with stress-induced opioid system activation in multiple ROIs, accounting for up to 14.5% and 5.4%, respectively, of the variance in regional activation. The associations were most robust among females, where combined they accounted for up to 25.0% of the variance among the ROIs. We conclude that there is a pathophysiologic link between polygenic risk for MDD and OUD and opioid system activity, as evidenced by PRS with unique and overlapping regional associations with this neurotransmitter system. This link could help to explain the high rate of comorbidity of MDD and OUD and suggests that opioid-modulating interventions could be useful in treating MDD and OUD, both individually and jointly.