Research Report
Brain-derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males

https://doi.org/10.1016/j.molbrainres.2005.07.008Get rights and content

Abstract

Data from animal studies and from genetic scans in humans suggest that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be involved in the mechanisms underlying substance abuse. The present study tested the hypothesis that the BDNF-gene Val66Met polymorphism is associated with substance abuse. We studied this polymorphism in 103 methamphetamine- and 200 heroin-dependent cases and 122 normal controls. We also considered the association of this polymorphism with age of onset of substance abuse in the heroin-dependent cases. Significant differences in BDNF Val66Met genotype distribution were found between subjects dependent on methamphetamine (P = 0.046) or heroin (P = 0.045) and controls, suggesting that the lower 66Met carrier frequency is associated with substance abuse. Furthermore, in the heroin-dependent group, the Val/Val homozygotes had a later onset of substance abuse compared with the Met allele carriers. The results suggest that the BDNF Val66Met polymorphism or a nearby locus may be involved in the pathogenesis of substance abuse. Our findings support previous genetic scan results showing that BDNF may contribute to substance abuse vulnerability.

Introduction

Substance abuse is among the most prevalent psychiatric disorders in males and impacts significantly on mortality and physical and social morbidity. It is known as substance dependence, if substance abuse is allowed to progress to long-term, repetitive self-administration. Although the underlying pathogenesis of substance abuse is still unknown, numerous twin and family studies have shown that vulnerability to substance abuse has a robust genetic component, which has general and specific components for each drug abused [23], [24].

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor-related family of neutrophins, is widely expressed in the adult mammalian brain [8], [17] and accumulating evidence indicates that it may be involved in the mechanisms underlying substance abuse. Data derived from animal studies have demonstrated that BDNF modulates dopaminergic and serotonergic functions that are heavily linked to substance abuse [4], [15]. Furthermore, studies involving BDNF administration or BDNF genetic knockouts have shown that this factor can alter cocaine and methamphetamine preference or drug-induced behaviors in animals [7], [9], [14], [18]. In 2001, Uhl et al. [22] studied 1004 subjects and 1494 single-nucleotide polymorphisms to scan vulnerability genes for polysubstance abuse, and found that positive markers flank the BDNF gene. They further demonstrated that a dinucleotide-repeat polymorphism located close to the 5′ end of the BDNF gene was also associated with drug-abuse vulnerability.

The above findings suggest that BDNF may represent an appropriate candidate gene that confers risk for substance abuse. The human BDNF gene has been mapped to chromosome 11 [16]. Recently, a common single-nucleotide polymorphism (G196A; rs6265) in the BDNF gene that results in a valine (Val) to methionine (Met) substitution in the prodomain has been shown to effect intracellular trafficking and activity-dependent secretion of BDNF [3], [5]. In the current investigation, the relationship between the BDNF-gene Val66Met polymorphism and methamphetamine or heroin dependence was investigated in a male sample population. In addition, we also considered whether this polymorphism affects the age of onset of substance abuse.

Section snippets

Subjects

A total of 103 methamphetamine-dependent and 200 heroin-dependent subjects were enrolled in this study. The methamphetamine-dependent subjects were inmates at the Taiwan Taipei Detention Center, with a confirmed diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, as interpreted by a psychiatrist at interview and described in our previous report [21]. The 200 heroin-dependent cases were recruited from a psychiatric hospital with the

Results

The mean ages of methamphetamine-dependent cases (27.8 ± 6.8 years), heroin-dependent cases (28.6 ± 6.7 years), and controls (29.8 ± 8.5 years) were similar (P = 0.072). The genotype and allele frequencies for the BDNF Val66Met genetic polymorphism for the three groups are presented in Table 1. The distribution for the genotypes of the BDNF Val66Met for each of the three groups was in Hardy–Weinberg equilibrium. Significant differences were found between the genotype distribution in the control

Discussion

The results of this study demonstrate that for our sample of Chinese men, BDNF Val66Met may be associated with vulnerability to substance abuse, chiefly methamphetamine or heroin dependence, and may affect age of onset of substance abuse. These positive associations in our study could have been due to chance or a stratification effect in the sample collection, and further study in independent samples is needed to confirm our findings. Our findings are in line with the report by Uhl et al. [22]

Acknowledgments

This work was supported by Grant DOH89-TD-1095, provided by the Department of Health, Taiwan and Grant VGH89-398-15, provided by the Taipei Veterans General Hospital. The authors wish to thank Mr. Chiou-Ting Feng, Tsung-Ho Liu, and the staff at the Taiwan Taipei Detention Center for their assistance with sample collection.

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