Does polygenic risk for substance-related traits predict ages of onset and progression of symptoms?

Background and AimsGenetic risk can influence disease progression. We measured the impact of genetic risk for substance use disorders (SUDs) on substance use onset and progression of symptoms. Design, Setting, ParticipantsUsing findings from genome-wide association studies (GWASs) of alcohol use disorder (AUD), opioid use disorder (OUD) and smoking trajectory (SMK) as discovery samples, we calculated polygenic risk scores (PRSs) in a deeply phenotyped independent target sample. Participants in the target sample were recruited from 2000 to 2020 from US inpatient or outpatient settings or through advertisements and comprised 5692 European-ancestry individuals (EUR) (56.2% male) and 4918 African-ancestry individuals (AFR) (54.9% male). MeasurementsThis study measured age of first substance use, regular use, reported problems and dependence diagnosis and progression from regular use to onset of problems and dependence for alcohol, opioids and smoking. We examined the contribution of PRS to each milestone and progression measure. FindingsEUR and males reported an earlier onset and shorter progression times than AFR and females, respectively. Among EUR, higher AUD PRS predicted earlier onset and more rapid progression to alcohol-related milestones (P < 0.001). Although the AUD PRS was a stronger moderator of problem onset among females (P = 0.017), it was more predictive of the progression to problems among males (P = 0.005). OUD and SMK PRS in EUR also predicted earlier onset of the respective milestones (P < 0.001). Among AFR, where power is lower due to the smaller discovery sample, AUD PRS predicted age of regular alcohol use (P = 0.039) and dependence (P = 0.001) and progression from regular use to diagnosis (P = 0.045), while SMK PRS predicted earlier age of initiation (P = 0.036). ConclusionsGenetic risk for SUDs appears to predict substance use milestones and symptom progression among European-ancestry individuals and, to a lesser extent, African-ancestry individuals.

Automated summary

This study investigated the impact of genetic risk for substance use disorders (SUDs) on the onset and progression of substance use. The results showed that European-ancestry individuals and males had an earlier onset and quicker progression of substance use, and the polygenic risk scores (PRSs) had predictive value for substance use milestones and symptom progression. In African-ancestry individuals, PRSs also predicted some substance use milestones, albeit to a lesser extent due to a smaller discovery sample.