The ætiology of substance-use disorders is multifactorial, with the genetic, personality and environmental factors interacting in a complex manner during the progression of addiction from initial predisposition to the development of substance dependence. This study aimed to explore, for the first time, the demographics, impulsive personality traits, and genetic influences on heroin dependence in Sri Lanka.
Data on demographics and drug-use patterns were collected using an interviewer administered questionnaire. Two dimensions of impulsivity, rash impulsivity and reward sensitivity, were assessed using self-reported measures. Initially, the personality measures were translated and validated for Sinhalese speaking population; all measures demonstrated adequate psychometric properties with factor structures, and reliability indices were consistent with those of the original versions. The severity of substance use was assessed against DSM-IV criteria for heroin dependence, the Alcohol Use Disorders Identification Test (AUDIT) and the Fagerstrom Test for Nicotine Dependence (FTND). Nineteen candidate-gene polymorphisms of GABA-, opioid- and dopamine-facilitated pathways of the brain reward system, which is the neural substrate for addiction, were genotyped in an ethnically distinct and homogenous Sinhalese male heroin-dependent population that was matched for age and ethnicity with a highly screened control sample in which subjects exhibited virtually no substance use.
The majority of participating drug users were young or middle aged with low levels of education. A significant proportion had experienced childhood delinquency and a deprived upbringing. The majority of participants had started substance use with alcohol and nicotine, followed by cannabis, before they went onto abuse heroin. Poly-drug abuse was common, with
widespread use of nicotine and alcohol. One striking feature was that, unlike in most other countries, injection drug use was scarce despite lifetime prevalence being higher than previously reported in Sri Lanka. The commonest reason given for initiating illicit-substance use was to seek excitement, which is consistent with impulsive/thrill-seeking personality. There was a high prevalence of familial substance use, which indicates either environmental or genetic influences, or both, on drug use in this population. Risky sexual behaviour was common, which entails an enhanced risk for developing and spreading sexually transmitted diseases.
The study highlighted the importance of exploring different dimensions of impulsivity with regard to substance use. The use of a two-factor model of impulsivity provided additional, novel important information about substance-use behaviours. The diagnosis of dependence was associated with both higher rash-impulsiveness and reward sensitivity, while heroin dependence-associated sub-phenotypes such as high-risk behaviour that included escalating heroin consumption, injecting heroin use, hazardous drinking, low treatment-seeking, and risky sexual behaviour were associated only with high rash-impulsiveness. An early onset of drug use was associated with reward sensitivity.
Using both conventional direct association analysis and novel, biologically relevant indirect and epistatic association strategies the current study revealed significant involvement of GABA, dopamine and opioid polymorphisms in heroin dependence and associated behaviour. There was evidence for direct associations with heroin dependence of individual SNPs GABRA6-rs3219151 and GABAG2- rs211013; OPRM1-rs1799971 and OPRM1 rs563649; and of certain haplotypes “CA” and “CG” of GABAG2-rs211014 and GABAG2-rs211013. There was also evidence for indirect associations mediated through impulsive personality (GABAG2-rs211013, GABAG2- rs211014 via fun-seeking personality, and DRD2-rs1079597 via sensitivity to reward), as well as an epistatic association between the GABRG2 and OPRM1 genes that is biologically pertinent.
In summary, during this study I successfully translated and validated three widely used instruments used to measure impulsive personality into Sinhalese, which can be used in future research. While impulsivity in general is known to be associated with substance abuse and dependence, the proposed 2-factor model of impulsivity provided additional information regarding predisposition to addiction. This justifies the use of this model of impulsivity in future research. I identified important risk factors (e.g., low education background, certain high risk occupations, childhood delinquency, and positive family history) and hazardous behaviours (poly-drug use, injecting drug use, and risky sexual behaviour) associated with substance abuse. Assessment of these attributes should be considered in future prevention strategies. This study provided significant evidence for a genetic basis for heroin dependence, particularly mediated by reward-pathway genes. The findings highlight the importance of using multiple strategies with biological foundations, such as mediation and epistatic analyses, in addition to conventional direct association analyses.