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Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders

Molecular Psychiatry (2024)Cite this article

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Abstract

Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, Neffective = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective = 296,974), cannabis use disorder (CanUD, Neffective = 161,053), opioid use disorder (OUD, Neffective = 57,120), and problematic tobacco use (PTU, Neffective = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (rg = 0.26, p = 7.55 × 10−18), CanUD (rg = 0.37, p = 8.21 × 10−37), OUD (rg = 0.20, p = 1.50 × 10−3), and PTU (rg = 0.29, p = 8.53 × 10−12). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p = 8.21 × 10−4; pain-outcome: beta = 0.07, p = 0.018), CanUD (pain-exposure: beta = 0.58, p = 2.70 × 10−6; pain-outcome: beta = 0.05, p = 0.014) and PTU (pain-exposure: beta = 0.43, p = 4.16 × 10−8; pain-outcome: beta = 0.09, p = 3.05 × 10−6) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1 rs7652746 (ppleiotropy = 2.69 × 10−8), and CADM2 rs1248857 (ppleiotropy = 1.98 × 10−5). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity.

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Fig. 1
Fig. 2: Bi-directional two-sample Mendelian Randomization analysis between multisite chronic pain and substance use disorders.
Fig. 3: Brain-wide association study of IHO1 rs7652746 and CADM2 rs1248857.

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Data availability

All data are reported in the manuscript and its supplemental material. For any additional queries, please reach out to the corresponding author. Genome-wide data used in this article are publicly available (MCP: https://researchdata.gla.ac.uk/822/, SUDs: dbGaP phs001672.v1.p1, https://www.ncbi.nlm.nih.gov/gap/).

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Acknowledgements

The authors acknowledge support from the Horizon 2020 Marie Sklodowska-Curie Individual Fellowship from the European Commission (101028810), the National Institutes of Health (R33 DA047527, R21 DC018098, RF1 MH132337, K99 AG078503, T32 MH014276, T32 AA02825, K01 DA051759), Alzheimer’s Association Research Fellowship (AARF-22-967171), and One Mind. We thank the participants and the investigators involved in the UK Biobank, Million Veteran Program, and the Psychiatric Genomics Consortium for making their data publicly available.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    Dora Koller, Eleni Friligkou, Brendan Stiltner, Gita A. Pathak, Solveig Løkhammer, Daniel F. Levey, Hang Zhou, Joseph D. Deak, Joel Gelernter & Renato Polimanti

  2. Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA

    Dora Koller, Eleni Friligkou, Brendan Stiltner, Gita A. Pathak, Daniel F. Levey, Hang Zhou, Joseph D. Deak, Joel Gelernter & Renato Polimanti

  3. Department of Genetics, Microbiology, and Statistics, Faculty of Biology, University of Barcelona, Catalonia, Spain

    Dora Koller

  4. NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway

    Solveig Løkhammer

  5. Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    Solveig Løkhammer

  6. Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, USA

    Alexander S. Hatoum

  7. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Rachel L. Kember & Henry R. Kranzler

  8. Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 4, Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA

    Rachel L. Kember & Henry R. Kranzler

  9. Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Jorien L. Treur

  10. Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA

    Emma C. Johnson

  11. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

  12. VA San Diego Healthcare System, San Diego, CA, USA

    Murray B. Stein

  13. Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

  14. Department of Genetics, Yale School of Medicine, New Haven, CT, USA

    Joel Gelernter

  15. Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA

    Joel Gelernter

  16. Wu Tsai Institute, Yale University, New Haven, CT, USA

    Joel Gelernter & Renato Polimanti

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  1. Dora Koller
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  2. Eleni Friligkou
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  3. Brendan Stiltner
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Contributions

DK and RP designed the study. DK analyzed the data, and wrote the manuscript draft. DFL, HZ, ASH, JDD, RLK, HRK, MBS and JG provided data. All the other authors provided critical feedback, context interpretation, draft revision, and editing. RP supervised the study, reviewed, and edited the manuscript.

Corresponding authors

Correspondence to Dora Koller or Renato Polimanti.

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Competing interests

RP reports a research grant from Alkermes. RP and JG are paid for their editorial work in the journal Complex Psychiatry. JG and HRK hold US patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued January 26, 2021. HRK is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to 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. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Clexio, Delix Pharmaceuticals, EmpowerPharm, Engrail Therapeutics, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech; has stock options in Oxeia Biopharmaceuticals and EpiVario; and has been paid for editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). The other authors declare no competing interests.

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Koller, D., Friligkou, E., Stiltner, B. et al. Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02446-3

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  • DOI: https://doi.org/10.1038/s41380-024-02446-3

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