Genomics and epigenomics of substance use disorders: An introduction

Abstract

Substance use disorders (SUD) are common conditions around the world, with important health and societal impacts, particularly in the burden of disease (disability-adjusted life years) (Whiteford, Ferrari, Degenhardt, Feigin, & Vos, 2015). The Global Burden of Disease Study estimated the global number of cases for SUD for several substances as follows: 94.8 million for alcohol, 17.2 million for amphetamine, 15.5 million for opioids, and 13.1 million for cannabis (Whiteford, 2015). In the United States, the lifetime and 12-month prevalences of SUD were 9.9% and 3.9%, respectively (Grant et al., 2016). In addition, polysubstance use is an important challenge in the field of addiction research (Whiteford et al., 2015). SUD are complex psychiatric disorders that result from the interaction of genetic, epigenetic, and environmental risk factors. Several studies have shown an important role for genetic factors in the etiology of major SUDs, with an estimated heritability of 65% for cocaine, 59% for nicotine, 51% for cannabis, and 50% for alcohol (Wang, Kapoor, & Goate, 2012). In the last decades, many candidate gene and genome-wide association studies (GWAS) have been performed to identify those genetic risk factors that underlie SUD, highlighting some relevant genes for the development of dependence on several drugs of abuse like alcohol (e.g., ADH1B, ADH2C, and ALDH2), nicotine (e.g., CHRNA5), and opioids (e.g., OPRM1) (recently reviewed by Lopez-Leon, Gonz alez-Giraldo, Wegman-Ostrosky, & Forero, 2021). Furthermore, some studies have started to identify genetic risk factors that are shared by several SUD and comorbid psychiatric disorders (Cabana-Domínguez, Shivalikanjli, Fernàndez-Castillo, & Cormand, 2019; Gurriar an et al., 2019). However, the genetic risk variants identified so far explain only a small fraction of the heritability of this complex disorder, and hence further studies and larger sample sizes are needed. Recent research has focused also on epigenetics to understand the interplay between environmental and genetic factors and druginduced changes involved in the remodeling of brain circuits and functional changes that underlie the transition from use to dependence. Repeated drug use has been shown to induce chromatin and histone modifications and alterations in DNA methylation that contribute to stable gene expression changes involved in these mechanisms, and that are also relevant for relapse in drug use (Beayno, El Hayek, Noufi, Tarabay, & Shamseddeen, 2019; Hamilton & Nestler, 2019; Werner, Altshuler, Shaham, & Li, 2021). Furthermore, studies investigating the role of miRNAs have highlighted miR-124 and miR-181, among others, in the development of the addictive process (Gowen et al., 2021). This special issue includes a total of seven works (CabreraMendoza et al., 2021; Gerring, Vargas, Gamazon, & Derks, 2020; Lai et al., 2020; Maldonado et al., 2021; Markunas et al., 2020; Soundararajan et al., 2021; Vilar-Rib o et al., 2020) that cover different topics on the genomics and epigenomics of SUD, one of them a review and the rest original research articles. We open our issue with a review paper, where Maldonado et al. (2021) examine how behavioral genetic research has contributed to advance our understanding of the links between genes, environment, and behavior, which conform the substrate of resilience and vulnerability to drug addiction. The fact that not all individuals who use drugs develop addiction, even if access to the substance is present, poses an interesting question on the biological basis of this phenotype. The authors start by reviewing the genetics of drug addiction, they continue with epigenetic factors that influence both resilience and vulnerability, and they conclude with focus on miRNAs as potential biomarkers based on their capacity to be secreted extracellularly and to the systemic circulation. They also report novel approaches to alter miRNA expression, like antagomiRs, sponges, or Tough Decoy inhibitors (TuD), which may pave the way to new therapeutic tools. The six research papers of the issue cover a broad range of substances, including tobacco, alcohol, cocaine and cannabis. State-ofthe-art methodologies are used, including genome-wide admixture mapping, integration of genetic variation and expression data through system-based analysis, Mendelian randomization to infer causality between phenotypes, genetic correlation, polygenic risk score analysis, or co-expression networks. Conceptually, three of the research papers put their focus on the genetic basis of substance use disorders based on GWAS data, two other works examine the presence of methylation changes in the blood of patients with alcohol or cannabis use disorders, and the last work aims at identifying pharmacological treatments for SUD and suicide based on gene expression data and drug repositioning. Vilar-Rib o et al. (2020) address the important topic of genetic overlap in psychiatric disorders. They use different tools to explore the shared genetics between SUD and attention-deficit hyperactivity disorder (ADHD), two conditions that are frequently comorbid. The results point at a common genetic background between ADHD and SUD and support the causal effect of the liability to ADHD on the risk for SUD, specifically smoking and lifetime cannabis use. Interestingly, a causal effect from cannabis use to ADHD risk was also observed for the first time. Finally, investigation of subjects with ADHD and from the general population revealed a shared genetic background Received: 29 April 2021 Accepted: 4 May 2021