Genome-wide analyses reveal shared genetic architecture and novel risk loci between opioid use disorder and general cognitive ability

Opioid use disorder (OUD), a serious health burden worldwide, is associated with lower cognitive function. Recent studies have demonstrated a negative genetic correlation between OUD and general cognitive ability (COG), indicating a shared genetic basis. However, the specific genetic variants involved, and the underlying molecular mechanisms remain poorly understood. Here, we aimed to quantify and identify the genetic basis underlying OUD and COG. We quantified the extent of genetic overlap between OUD and COG using a bivariate causal mixture model (MiXeR) and identified specific genetic loci applying conditional/conjunctional FDR. Finally, we investigated biological function and expression of implicated genes using available resources. We estimated that ~94% of OUD variants (4.8k out of 5.1k variants) also influence COG. We identified three novel OUD risk loci and one locus shared between OUD and COG. Loci identified implicated biological substrates in the basal ganglia. We provide new insights into the complex genetic risk architecture of OUD and its genetic relationship with COG. •Ninety four percent of opioid use disorder (OUD) genetics is captured by genetics of general cognitive abilityability (COG).•The shared portion of genetics between OUD and COG exhibits highly negative genetic correlation.•COG is twice as polygenic as OUD.•OUD is similar in polygenicity as ADHD.•Novel genetic loci identified for OUD and COG implicates genes expressed in reward circuitry.