260. Prescription medication use, healthcare utilisation and genetic risk for addiction: a phenome-wide association and Mendelian randomization study

Abstract

Abstract Background Substance Use Disorders (SUDs) are major contributors to global morbidity and premature mortality. While their adverse physical and psychiatric sequalae are widely attributed to toxic effects of substance exposure, accumulating evidence suggests that inherited liability to addiction also shapes broader patterns of health. Prescription medication use is a universal health-related behaviour, which reflects how individuals interact with the healthcare system. However, it remains unknown whether genetic risk for addiction is expressed in routine medical treatment, particularly in populations with low prevalence of diagnosed SUD. Aims & Objectives We aimed to determine whether genetic liability to alcohol (AUD), tobacco (TUD), opioid (OUD), cannabis (CanUD) and cocaine (CocUD) use disorders is associated with patterns of prescription medication use, comorbidity, and healthcare utilisation. We hypothesized that genetic risk for SUD confers increased use of medications with dependence potential within a causal Mendelian randomization (MR) framework. Method We analyzed 377,102 unrelated UK Biobank (UKB) participants of inferred European ancestry with available genotyping, medication data, and linked electronic health records. Polygenic risk scores (PRS) were derived from the largest available SUD genome-wide association studies (Ncases=20,686-163,734, excluding UKB) using SBayesRC. We conducted a medication phenome-wide association study across 261 medications grouped into 30 therapeutic classes using multivariable logistic regression adjusted for demographic and genetic covariates. Parallel phenome-wide analyses were performed across 868 ICD-10-derived PheCodes and healthcare utilisation measures including polypharmacy, primary care prescribing and hospitalizations. Bidirectional two-sample MR and multivariable MR were used to assess directionality. Results All five PRSSUD were significantly associated with ICD-10 alcohol- and tobacco-related diagnoses (odds ratios [OR] per SD increase in PRS 1.04-1.26; pFDR≤1.16*10-3). Ninety-six medications across 23 classes were associated with at least one PRSSUD with predominantly positive effects. Associations spanned analgesics, cardiovascular (e.g. statins, antithrombotics), gastrointestinal and respiratory agents. All PRSSUD were associated with increased use of opioids (OR=1.04-1.16, pFDR≤1.33*10-5), paracetamol (OR=1.01-1.06; pFDR≤4.49*10-3) and antidepressants (OR=1.03-1.11; pFDR≤7.05*10-4). Fifty-three medications and 21 classes remained FDR-significant after adjustment for alcohol consumption, smoking and psychiatric comorbidity. Phenome-wide analyses revealed parallel associations with cardiorespiratory, musculoskeletal and psychiatric diagnoses. Participants in the top PRSSUD quantile had 1.4-9.6% (pFDR≤0.04) more inpatient hospital admissions compared with the bottom quantile, alongside higher polypharmacy, primary care prescriptions and illness burden. MR supported directional effects of addiction liability on medication use. A two-fold increase in genetically-predicted CocUD was associated with higher use of opioids (OR=1.92; pFDR≤1.83*10-10) and antidepressants (OR=1.54; pFDR≤3.44*10-7), which persisted after accounting for pain, depression and anxiety. Genetically-predicted TUD was associated with increased use of antithrombotics (OR=1.24; pFDR ≤ 3.15*10-4) and vasodilators (OR=1.74; pFDR≤8.48*10-5). Reverse MR provided no evidence for bidirectional relationships. Discussion & Conclusions In a large population cohort with low SUD prevalence, genetic liability to addiction was associated with increased prescription medication use and healthcare utilisation including routine medical pharmacotherapies without dependence potential. MR supported addiction liability acting upstream of medication-use within a causal framework. Our findings advance conceptualization of addiction as a systemic health risk and underscore the importance of general healthcare settings as a potential point of contact for individuals at elevated addiction risk.