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. 2024 May 29;14(1):221.
doi: 10.1038/s41398-024-02923-x.

Disentangling heterogeneity in substance use disorder: Insights from genome-wide polygenic scores

Laura Vilar-Ribó #  1   2   3 , Judit Cabana-Domínguez #  1   2   3 , Silvia Alemany  1   2   3 , Natalia Llonga  1   2   3   4 , Lorena Arribas  1   2 , Lara Grau-López  1   2   3   5   6 , Constanza Daigre  1   2   3   5   6 , Bru Cormand  4   7   8   9 , Noèlia Fernàndez-Castillo  4   7   8   9 , Josep Antoni Ramos-Quiroga  1   2   3   5   6 , María Soler Artigas  10   11   12   13 , Marta Ribasés  14   15   16   17
Affiliations

Disentangling heterogeneity in substance use disorder: Insights from genome-wide polygenic scores

Laura Vilar-Ribó et al. Transl Psychiatry. .

Abstract

Substance use disorder (SUD) is a global health problem with a significant impact on individuals and society. The presentation of SUD is diverse, involving various substances, ages at onset, comorbid conditions, and disease trajectories. Current treatments for SUD struggle to address this heterogeneity, resulting in high relapse rates. SUD often co-occurs with other psychiatric and mental health-related conditions that contribute to the heterogeneity of the disorder and predispose to adverse disease trajectories. Family and genetic studies highlight the role of genetic and environmental factors in the course of SUD, and point to a shared genetic liability between SUDs and comorbid psychopathology. In this study, we aimed to disentangle SUD heterogeneity using a deeply phenotyped SUD cohort and polygenic scores (PGSs) for psychiatric disorders and related traits. We explored associations between PGSs and various SUD-related phenotypes, as well as PGS-environment interactions using information on lifetime emotional, physical, and/or sexual abuse. Our results identify clusters of individuals who exhibit differences in their phenotypic profile and reveal different patterns of associations between SUD-related phenotypes and the genetic liability for mental health-related traits, which may help explain part of the heterogeneity observed in SUD. In our SUD sample, we found associations linking the genetic liability for attention-deficit hyperactivity disorder (ADHD) with lower educational attainment, the genetic liability for post-traumatic stress disorder (PTSD) with higher rates of unemployment, the genetic liability for educational attainment with lower rates of criminal records and unemployment, and the genetic liability for well-being with lower rates of outpatient treatments and fewer problems related to family and social relationships. We also found evidence of PGS-environment interactions showing that genetic liability for suicide attempts worsened the psychiatric status in SUD individuals with a history of emotional physical and/or sexual abuse. Collectively, these data contribute to a better understanding of the role of genetic liability for mental health-related conditions and adverse life experiences in SUD heterogeneity.

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Conflict of interest statement

J.A.R.Q was on the speakers’ bureau and/or acted as a consultant for Biogen, Idorsia, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, Novartis, BMS, Medice, Rubió, Uriach, Technofarma, and Raffo in the last 3 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubió, Takeda, Bial, and Medice. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas, Psious, and Rubió. All other authors declare no biomedical financial interests or conflicts of interest.

Figures

Fig. 1
Fig. 1. Flowchart.
Flowchart with the different stages of the study including the recruitment and follow-up of the SUD sample. Sample size (n) refers to the number of individuals with at least one item of the interview available.
Fig. 2
Fig. 2. Heatmap for the results of the association between PGSs and SUD-related phenotypes.
Association pattern between 10 PGSs for psychiatric disorders, behavioural and related traits with the SUD-related phenotypes; *nominal significance p-values; **p-values that passed multiple testing correction using PhenoSpD (p < 1.46−03). ADHD Attention-deficit hyperactivity disorder, PTSD Post-traumatic stress disorder. The standardized coefficient corresponds to Beta for continuous variables, log(OR) for binary and ordinal variables, and log(IRR) for count variables.
Fig. 3
Fig. 3. Statistically significant result from the interaction analysis.
Interaction between PGS for suicide attempt and lifetime emotional, physical and/or sexual abuse in psychiatric status measured by the EuropASI index. The X-axis presents the PGS for a suicide attempt, and the Y-axis shows the residuals from an ordinal regression model with psychiatric status as outcome adjusted for age, sex, genotyping batch, and the 10 first principal components for those individuals who suffered lifetime abuse (in green) and those who did not (in pink).
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