Opioid dependence (OD) is epidemic in the United States and it is associated with a variety of adverse health effects. Its estimated heritability is ~50%, and recent genome-wide association studies have identified more than a dozen common risk variants. However, there are no published studies of rare OD risk variants. In this study, we analyzed whole-exome sequencing data from the Yale-Penn cohort, comprising 2,100 participants of European ancestry (EUR; 1,321 OD cases) and 1,790 of African ancestry (AFR; 864 cases). A novel low-frequency variant (rs746301110) in the RUVBL2 gene was identified in EUR (p=6.59*10-10). Suggestive associations (p<1*10-5) were observed in TMCO3 in EUR, in NEIL2 and CFAP44 in AFR, and in FAM210B in the cross-ancestry meta-analysis. Gene-based collapsing tests identified SLC22A10, TMCO3, FAM90A1, DHX58, CHRND, GLDN, PLAT, H1-4, COL3A1, GPHB5 and QPCTL as top genes (p<1*10-4) with most associations attributable to rare variants and driven by the burden of predicted loss-of-function and missense variants. This study begins to fill the gap in our understanding of the genetic architecture of OD, providing insights into the contribution of rare coding variants and potential targets for future functional studies and drug development.

J.G. is paid for his editorial work on the journal Complex Psychiatry. J.G. and H.R.K. hold US patent 10,900,082 titled: "Genotype-guided dosing of opioid agonists," issued January 26, 2021. H.R.K. is a member of advisory boards for Altimmune, Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Enthion Pharmaceuticals, and Clearmind Medicine; a consultant to Altimmune and Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics.

The authors are supported by grants from the National Institutes of Health (NIH) (R01 DA12890, R01 AA026364, R01 AA11330, R01 DA037974, P30 DA046345, P50 AA012870, U54 AA027989, RM1 HG011558, and R01 AA030056) and the U.S. Department of Veterans Affairs (1I01CX001849 and I01 BX004820).

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 Yale-Penn study was approved by the IRBs at all participating clinical sites. All participants provided written informed consent.

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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 in the present study are available upon reasonable request to the authors.