Abstract
Substance dependence is a frequently observed comorbid disorder in schizophrenia, but little is known about genetic factors possibly shared between the two psychotic disorders. GABRB2, a schizophrenia candidate gene coding for GABAA receptor β2 subunit, is examined for possible association with heroin dependence in Han Chinese population. Four single nucleotide polymorphisms (SNPs) in GABRB2, namely rs6556547 (S1), rs1816071 (S3), rs18016072 (S5), and rs187269 (S29), previously associated with schizophrenia, were examined for their association with heroin dependence. Two additional SNPs, rs10051667 (S31) and rs967771 (S32), previously associated with alcohol dependence and bipolar disorder respectively, were also analyzed. The six SNPs were genotyped by direct sequencing of PCR amplicons of target regions for 564 heroin dependent individuals and 498 controls of Han Chinese origin. Interestingly, it was found that recombination between the haplotypes of all-derived-allele (H1; OR = 1.00) and all-ancestral-allele (H2; OR = 0.74) at S5-S29 junction generated two recombinants H3 (OR = 8.51) and H4 (OR = 5.58), both conferring high susceptibility to heroin dependence. Additional recombination between H2 and H3 haplotypes at S1-S3 junction resulted in a risk-conferring haplotype H5 (OR = 1.94x109). In contrast, recombination between H1 and H2 haplotypes at S3-S5 junction rescued the risk-conferring effect of recombination at S5-S29 junction, giving rise to the protective haplotype H6 (OR = 0.68). Risk-conferring effects of S1-S3 and S5-S29 crossovers and protective effects of S3-S5 crossover were seen in both pure heroin dependent and multiple substance dependence subgroups. In conclusion, significant association was found with haplotypes of the S1-S29 segment in GABRB2 for heroin dependence in Han Chinese population. Local recombination was an important determining factor for switching haplotypes between risk-conferring and protective statuses. The present study provide evidence for the schizophrenia candidate gene GABRB2 to play a role in heroin dependence, but replication of these findings is required.
Highlights
Substance dependence is a common comorbid disorder in schizophrenia with the highest abuse rate from alcohol (43.1%-65%), followed by cannabis (50.8%), nicotine (28.5%), and cocaine dependence (23%) [1]
Mechanisms involved in the comorbidity of schizophrenia and substance dependence are poorly understood, but much of the proposed models agree on the complex interaction between biological and genetic factors: (1) existence of common genetic risk factors in the dopamine (DA) pathway that leads to the concomitant onset of both disorders; (2) the self-medication hypothesis which states that substance abuse is used as a means to alleviate negative and deficit symptoms of schizophrenia [2]
We examined the role of in GABRB2 in susceptibility to heroin dependence in the Han Chinese population
Summary
Substance dependence is a common comorbid disorder in schizophrenia with the highest abuse rate from alcohol (43.1%-65%), followed by cannabis (50.8%), nicotine (28.5%), and cocaine dependence (23%) [1]. The most widely expressed hetero-metameric combinations of GABAA receptor comprises of α1, β2, and γ2 subunits, which are encoded by the α1 subunit (GABRA1), β2 subunit (GABRB2), and ү2 subunit (GABRG2) genes [3]. Such a diverse localization of GABAA β2 subunit in the mammalian brain raised the possibility on the possible overlap in the genetic susceptibility of schizophrenia and substance dependence. In case-control studies, significant association of GABRB2 has been observed with various psychotic disorders including autism [7], bipolar disorder [8], epilepsy [9], schizophrenia [10,11,12,13], and alcohol dependence [14]
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