Importance: Persons with substance use disorders (SUD) often suffer from additional comorbidities, including psychiatric conditions and physical health problems. Researchers have explored this overlap in electronic health records (EHR) using phenome wide association studies (PheWAS) to characterize how different indicators are related to all conditions in an individuals EHR. However, analyses have been largely cross-sectional in nature. Objective: To characterize whether various social and genetic risk factors are associated with time to comorbid diagnoses in electronic health records (EHR) after the first diagnosis of SUD. Design: Leveraging those with EHR and whole-genome sequencing data in All of Us (N = 287,012), we explored whether social determinants of health are associated with lifetime risk of SUD. Next, within those with a diagnosed SUD (N = 17,460), we examined whether polygenic scores (PGS) were associated with time to comorbid diagnoses performing a phenome-wide survival analysis. Setting: Participating health care organizations across the United States. Participants: Participants in the All of Us Research Program with available EHR and genomic data, Exposures: Social determinants of health and polygenic scores (PGS) for psychiatric and substance use disorders, Main Outcomes and Measures: Phecodes for diagnoses derived from International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from EHR. Results: Multiple social and demographic risk factors were associated with lifetime SUD diagnosis. Most strikingly, those reporting an annual income <$10K had 4.5 times the odds of having an SUD diagnosis compared to those reporting $100-$150K annually (OR = 4.48, 95% CI = 4.01, 5.01). PGSs for alcohol use disorders, schizophrenia, and post-traumatic stress disorder were associated with time to their respective diagnoses (HRAUD = 1.10, 95% CI = 1.06, 1.14; HRSCZ = 1.13, 95% CI = 1.06, 1.20; HRPTSD = 1.15, 95% CI = 1.08, 1.22). A PGS for ever-smoking was associated with time to subsequent smoking related comorbidities and additional SUD diagnoses HRSMOK = 1.6 to 1.16). Conclusions and Relevance: Social determinants, especially those related to income have profound associations with lifetime SUD risk. Additionally, PGS may include information related to outcomes above and beyond lifetime risk, including timing and severity.

Dr Harvey reported receiving personal fees from Boehringer Ingelheim, Bioexcel, Karuna Therapeutics, Minerva Neuroscience, Alkermes, Sunovion, and Roche; royalties from WCG Endpoint Solutions; and equity from i-Function outside the submitted work. No other disclosures were reported.

This study was supported in part by National Institute of Mental Health (R01MH125938: Drs Peterson, Bigdeli, Chatzinakos, and Meyers); the National Institute of Drug Abuse (R01DA050721: Dr Barr; R01DA060596: Drs Meyers, Barr, Chatzinakos, and Neale), and the National Institute on Alcohol Abuse and Alcoholism (R01AA030010: Drs Meyers, Barr, Chatzinakos, and Neale). Computing costs associated with this work was supported by R01MH125938 (PI: Peterson). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of SUNY Downstate Health Sciences University waived ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data produced are available online via the All of Us Researcher Workbench.