Abstract / Summary
Abstract Background Response to methadone maintenance therapy (MMT) varies widely, but its genetic basis remains poorly understood, particularly in non-European populations. We hypothesized that shared polygenic liability across psychiatric and substance use disorders contributes to earlier opioid use disorder (OUD) onset through specific pathways and predicts MMT response. Methods We analyzed 769 Iranian individuals with OUD receiving MMT. After quality control, subsets were used to: (i) test polygenic risk scores (PRS) for psychiatric, substance-use, and antidepressant response traits; and (ii) perform a genome-wide association study (GWAS) for both age of onset and methadone response, integrating locus-specific fine-mapping and MAGMA gene-based and pathway enrichment analyses. Results Higher MDD polygenic risk was associated with reduced odds of methadone treatment response and remained significant in a model jointly including bipolar disorder and schizophrenia PRSs; the latter PRSs were not independently significant. The age-of-onset of OUD GWAS identified a suggestive non-coding locus on chromosome 4 (β=−2.74, P = 1.69×10 − 6 ) and suggestive signals ( P = 1×10 − 5 to 5×10 − 5 ) near GLP1R , MAPK10 , PDE 4 B , TIA 1 and SNRPG. The methadone response GWAS identified suggestive loci in EPHA5 (OR = 1.81, P = 9.9×10 − 6 ) and HOMER1 (OR = 0.54, P = 1.6×10 − 5 ). Pathway analysis implicated branched-chain amino acid and fatty acid metabolism in age at onset (FDR<0.05), and TGF-β and JAK–STAT signaling in methadone response ( P =9.9×10⁻⁷–1.1×10⁻³; FDR<0.05). Conclusions Distinct but convergent polygenic and biological mechanisms shape opioid-use onset and methadone response, implicating psychiatric liability, metabolic regulation, and neuroimmune signaling as candidate mechanisms of clinical heterogeneity in OUD.