ALDH2 Gene: Its Effects on the Neuropsychological Functions in Patients with Opioid Use Disorder Undergoing Methadone Maintenance Treatment

Abstract

Objective: Patients with opioid use disorder (OUD) have impaired attention, inhibition control, and memory function. The aldehyde dehydrogenase 2 (ALDH2) gene has been associated with OUD and ALDH2 gene polymorphisms may affect aldehyde metabolism and cognitive function in other substance use disorder. Therefore, we aimed to investigate whether ALDH2 genotypes have significant effects on neuropsychological functions in OUD patients undergoing methadone maintenance therapy (MMT). Methods: OUD patients undergoing MMT were investigated and followed-up for 12 weeks. ALDH2 gene polymorphisms were genotyped. Connors' Continuous Performance Test (CPT) and the Wechsler Memory Scale-Revised (WMS-R) were administered at baseline and after 12 weeks of MMT. Multivariate linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between the ALDH2 genotypes and performance on the CPTs and WMS-R. Results: We enrolled 86 patients at baseline; 61 patients completed the end-of-study assessments. The GEE analysis showed that, after the 12 weeks of MMT, OUD patients with the ALDH2 *1/*2＋*2/*2 (ALDH2 inactive) genotypes had significantly higher commission error T-scores (p = 0.03), significantly lower hit reaction time T-scores (p = 0.04), and significantly lower WMS-R visual memory index scores (p = 0.03) than did patients with the ALDH2 1*/*1 (ALDH2 active) genotype. Conclusion: OUD patients with the ALDH2 inactive genotypes performed worse in cognitive domains of attention, impulse control, and memory than did those with the ALDH2 active genotype. We conclude that the ALDH2 gene is important in OUD and is associated with neuropsychological performance after MMT.

Integration of tissue-specific multi-omics data implicates brain targets for complex neuropsychiatric traits

“…ALDH2 is one of the major ALDH isozymes that catalyze the oxidation of dopamine. Impairment or inactivation of ALDH2 would accumulate a higher level of toxic dopamine metabolite, consequently contributing to neurocognitive dysfunction [35,36]. Brain atrophy and AD biomarkers changes were also observed from Aldh2-/-mice model [37].…”

SNP-based and haplotype-based genome-wide association on drug dependence in Han Chinese

“…The rs671 A allele may cause low ALDH2 enzyme activity and reduced metabolism, resulting in delayed clearance of drugs and increased plasma drug concentrations. ALDH2 is an important factor in opioid-use disorder and is associated with neuropsychological performance after methadone maintenance therapy [ 42 ]. There is thus compelling evidence indicating a role for ALDH2 rs671 in drug dependency.…”

FOXN3 and GDNF Polymorphisms as Common Genetic Factors of Substance Use and Addictive Behaviors

“…Twin (and other) studies suggested that most shared genetic and environmental factors may not be substance-specific [ 45 , 46 , 47 , 48 , 49 ], although genome-wide association studies often implicate genes involved in substance metabolism and subjective responses to specific drugs [ 50 , 51 ]. Identified genetic variants in addiction-related genes (e.g., aldehyde dehydrogenases [ ALDHs ], Gamma-Aminobutyric Acid Type A Receptor Alpha2 Subunit [ GABRA2 ], and DRD2/Ankyrin repeat and kinase domain containing 1 [ ANKK1 ]) were linked to dependence on various substances [ 52 , 53 , 54 , 55 ]. Gene network analysis showed immune signaling and extracellular signal-regulated protein kinases 1 and 2 ( ERK1/2 ) as novel genetic markers for multiple addiction phenotypes including alcohol, tobacco, and opioid use disorders [ 56 ].…”