Abstract
This study investigated the genetic and epigenetic mechanisms underlying the comorbidity of five substance dependence diagnoses (SDs; alcohol, AD; cannabis, CaD; cocaine, CoD; opioid, OD; tobacco, TD). A latent class analysis (LCA) was performed on 22,668 individuals from six cohorts to identify comorbid DSM-IV SD patterns. In subsets of this sample, we tested SD-latent classes with respect to polygenic overlap of psychiatric and psychosocial traits in 7659 individuals of European descent and epigenome-wide changes in 886 individuals of African, European, and Admixed-American descents. The LCA identified four latent classes related to SD comorbidities: AD + TD, CoD + TD, AD + CoD + OD + TD (i.e., polysubstance addiction, PSU), and TD. In the epigenome-wide association analysis, SPATA4 cg02833127 was associated with CoD + TD, AD + TD, and PSU latent classes. AD + TD latent class was also associated with CpG sites located on ARID1B, NOTCH1, SERTAD4, and SIN3B, while additional epigenome-wide significant associations with CoD + TD latent class were observed in ANO6 and MOV10 genes. PSU-latent class was also associated with a differentially methylated region in LDB1. We also observed shared polygenic score (PGS) associations for PSU, AD + TD, and CoD + TD latent classes (i.e., attention-deficit hyperactivity disorder, anxiety, educational attainment, and schizophrenia PGS). In contrast, TD-latent class was exclusively associated with posttraumatic stress disorder-PGS. Other specific associations were observed for PSU-latent class (subjective wellbeing-PGS and neuroticism-PGS) and AD + TD-latent class (bipolar disorder-PGS). In conclusion, we identified shared and unique genetic and epigenetic mechanisms underlying SD comorbidity patterns. These findings highlight the importance of modeling the co-occurrence of SD diagnoses when investigating the molecular basis of addiction-related traits.
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Acknowledgements
This study is supported by the National Institute on Drug Abuse, R33 DA047527. GAP acknowledges support from the Yale Biological Sciences Training Program (T32 MH014276), Alzheimer’s Association (AARF-22-967171), NIH National Institute of Aging (K99 AG078503), Yale Franke Fellowship in Science & Humanities, and Yale Women’s Faculty Forum Award. RP acknowledges grants from the National Institute of Mental Health (RF1 MH132337) and One Mind Rising Star Award. JDD acknowledges support from the National Institute on Drug Abuse K01 DA058807. DFL is funded by a Career Development Award from the US Department of Veterans Affairs Office of Research and Development (1IK2BX005058). HK acknowledges support from the Department of Veterans Affairs (VISN 4 MIRECC and I01 BX004820). JLMO acknowledges support from U.S. Department of Veterans Affairs via 1IK2CX002095 and NIDA R21 DA050160. JG reports support from the Department of Veterans Affairs (5IO1CX001849-04 and the VISN 1 New England MIRECC) and NIH/NIDA (R01 DA037974, R01 DA058862).
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GAP and RP designed the study. GAP analyzed the data. RHP, CO, FRW, JDD, EF, and GAP supported the data analysis. AL and YZN contributed to generating the Yale-Penn phenotypic and molecular data. JLM, DFL, HRK, JG, and RP supported the collection, assessment, or molecular assays of Yale-Penn cohort. GAP and RP wrote the manuscript. All the other authors provided critical feedback, context interpretation, draft revision, and editing. RP supervised the study and received the primary funding that supported the study.
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RP received a research grant from Alkermes outside the scope of the present study. RP and JG are paid for their editorial work on the journal Complex Psychiatry. JG and HRK are holders of U.S. patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued 26 January 2021. HRK is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Enthion Pharmaceuticals, and Clearmind Medicine; a consultant to Sobrera Pharmaceuticals and Altimmune; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics. FRW is an employee of Regeneron Pharmaceuticals with no conflict of interest related to any intellectual property of the company. The other authors have no competing interests to report.
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Pathak, G.A., Pietrzak, R.H., Lacobelle, A. et al. Epigenetic and genetic profiling of comorbidity patterns among substance dependence diagnoses. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03031-y
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DOI: https://doi.org/10.1038/s41380-025-03031-y