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1- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
2- School of medicine, Iran University of Medical Sciences, Tehran, Iran
3- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4- Research Center for Addiction and Risky Behaviors (ReCARB), Psychosocial Health Research Institute (PHRI), Iran University of Medical Sciences, Tehran, Iran.
2- School of medicine, Iran University of Medical Sciences, Tehran, Iran
3- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4- Research Center for Addiction and Risky Behaviors (ReCARB), Psychosocial Health Research Institute (PHRI), Iran University of Medical Sciences, Tehran, Iran.
Abstract:
Background: Opioid use disorder (OUD) is a major global health problem. Personality traits, particularly conscientiousness, have been linked to lower substance use in observational studies, but causal evidence is lacking. This study aimed to investigate whether genetically predicted conscientiousness has a causal link with OUD.
Methods: The study employed a two-sample Mendelian randomization (MR) framework using summary statistics from the largest available GWAS of conscientiousness (N = 234,880; Million Veteran Program) and OUD (20,686 cases, 77,026 controls; MVP and Psychiatric Genomics Consortium) in European ancestry participants. Thirteen independent single-nucleotide polymorphisms (SNPs) (P < 5 × 10⁻⁷, r² < 0.001, F > 10) were selected as instrumental variables. The primary causal estimate used is inverse-variance weighted (IVW) MR. Sensitivity analyses included weighted median, MR-Egger regression, weighted mode, simple mode, Cochran’s Q test, and leave-one-out analyses to assess pleiotropy and heterogeneity.
Results: IVW MR revealed a significant protective effect of genetically predicted conscientiousness on OUD risk (β = −0.493; 95% CI: −0.597 to −0.389; P = 7.8 × 10⁻²¹). Consistent effect sizes were observed across sensitivity analyses: weighted median (β = −0.468; 95% CI: −0.607 to −0.329; P = 5.3 × 10⁻¹¹), weighted mode (β = −0.467; 95% CI: −0.683 to −0.251; P = 1.2 × 10⁻³), and simple mode (β = −0.467; 95% CI: −0.692 to −0.242; P = 1.6 × 10⁻³). MR-Egger regression direction was consistent (β = −2.487; P = 0.526), with intercept P = 0.609 indicating no horizontal pleiotropy. Cochran’s Q tests indicated no heterogeneity (IVW Q = 1.22, P = 0.999; MR-Egger Q = 0.94, P = 0.999). Leave-one-out analysis confirmed the stability of causal estimates.
Conclusion: The current study provides robust evidence that higher genetically predicted conscientiousness causally reduces OUD risk. These findings suggest that self-regulatory personality traits act as protective factors and highlight potential behavioral targets for prevention strategies. These findings are not directly generalizable to non-European groups without replication. Future research should focus on cross-ancestry replication and trait subcomponents.
Methods: The study employed a two-sample Mendelian randomization (MR) framework using summary statistics from the largest available GWAS of conscientiousness (N = 234,880; Million Veteran Program) and OUD (20,686 cases, 77,026 controls; MVP and Psychiatric Genomics Consortium) in European ancestry participants. Thirteen independent single-nucleotide polymorphisms (SNPs) (P < 5 × 10⁻⁷, r² < 0.001, F > 10) were selected as instrumental variables. The primary causal estimate used is inverse-variance weighted (IVW) MR. Sensitivity analyses included weighted median, MR-Egger regression, weighted mode, simple mode, Cochran’s Q test, and leave-one-out analyses to assess pleiotropy and heterogeneity.
Results: IVW MR revealed a significant protective effect of genetically predicted conscientiousness on OUD risk (β = −0.493; 95% CI: −0.597 to −0.389; P = 7.8 × 10⁻²¹). Consistent effect sizes were observed across sensitivity analyses: weighted median (β = −0.468; 95% CI: −0.607 to −0.329; P = 5.3 × 10⁻¹¹), weighted mode (β = −0.467; 95% CI: −0.683 to −0.251; P = 1.2 × 10⁻³), and simple mode (β = −0.467; 95% CI: −0.692 to −0.242; P = 1.6 × 10⁻³). MR-Egger regression direction was consistent (β = −2.487; P = 0.526), with intercept P = 0.609 indicating no horizontal pleiotropy. Cochran’s Q tests indicated no heterogeneity (IVW Q = 1.22, P = 0.999; MR-Egger Q = 0.94, P = 0.999). Leave-one-out analysis confirmed the stability of causal estimates.
Conclusion: The current study provides robust evidence that higher genetically predicted conscientiousness causally reduces OUD risk. These findings suggest that self-regulatory personality traits act as protective factors and highlight potential behavioral targets for prevention strategies. These findings are not directly generalizable to non-European groups without replication. Future research should focus on cross-ancestry replication and trait subcomponents.
Type of Study: Original |
Subject:
Behavioral Neuroscience
Received: 2026/02/25 | Accepted: 2026/05/25
Received: 2026/02/25 | Accepted: 2026/05/25
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