title: GABRB2 Haplotype Association with Heroin Dependence in Chinese Population.
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.
authors.affiliation: Division of Life Science and Applied Genomics Center, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Yung Su
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Mental Health Institute, the Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.affiliation: Division of Life Science and Applied Genomics Center, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Wai-Kin
authors.initials: WK
authors.lastname: Mat
authors.affiliation: Division of Life Science and Applied Genomics Center, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.|Center for Statistical Science, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Shui-Ying
authors.initials: SY
authors.lastname: Tsang
authors.affiliation: The Second Affiliated Hospital of Jining Medical College, Jining, Shandong, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Su
authors.affiliation: The Second Affiliated Hospital of Jining Medical College, Jining, Shandong, China.
authors.forename: Xianfei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Division of Life Science and Applied Genomics Center, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Siu-Kin
authors.initials: SK
authors.lastname: Ng
authors.affiliation: Division of Life Science and Applied Genomics Center, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Division of Life Science and Applied Genomics Center, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Taobo
authors.initials: T
authors.lastname: Hu
authors.affiliation: Division of Life Science and Applied Genomics Center, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.|Center for Statistical Science, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Frank
authors.initials: F
authors.lastname: Pun
authors.affiliation: Mental Health Institute, the Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Mental Health Institute, the Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Tang
authors.affiliation: Mental Health Institute, the Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Mental Health Institute, the Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hao
authors.affiliation: Division of Life Science and Applied Genomics Center, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.|Center for Statistical Science, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.|State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xue
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D002681:China; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006556:Heroin Dependence / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C495710:GABRB2 protein, human; D011963:Receptors, GABA-A