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

Autor: Koller D; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. dora.koller@yale.edu.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA. dora.koller@yale.edu.; Department of Genetics, Microbiology, and Statistics, Faculty of Biology, University of Barcelona, Catalonia, Spain. dora.koller@yale.edu., Friligkou E; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA., Stiltner B; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA., Pathak GA; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA., Løkhammer S; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway., Levey DF; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA., Zhou H; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA., Hatoum AS; Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, USA., Deak JD; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA., Kember RL; Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 4, Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA., Treur JL; Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands., Kranzler HR; Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 4, Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA., Johnson EC; Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA., Stein MB; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.; VA San Diego Healthcare System, San Diego, CA, USA.; Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA., Gelernter J; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.; Wu Tsai Institute, Yale University, New Haven, CT, USA., Polimanti R; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. renato.polimanti@yale.edu.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA. renato.polimanti@yale.edu.; Wu Tsai Institute, Yale University, New Haven, CT, USA. renato.polimanti@yale.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Jul; Vol. 29 (7), pp. 2021-2030. Date of Electronic Publication: 2024 Feb 15.
DOI: 10.1038/s41380-024-02446-3
Abstrakt: 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, N effective  = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, N effective  = 296,974), cannabis use disorder (CanUD, N effective  = 161,053), opioid use disorder (OUD, N effective  = 57,120), and problematic tobacco use (PTU, N effective  = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (r g ) 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 (r g  = 0.26, p = 7.55 × 10 -18 ), CanUD (r g  = 0.37, p = 8.21 × 10 -37 ), OUD (r g  = 0.20, p = 1.50 × 10 -3 ), and PTU (r g  = 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 (p pleiotropy  = 2.69 × 10 -8 ), and CADM2 rs1248857 (p pleiotropy  = 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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