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Meta-analysis of GABRB2 polymorphisms and the risk of schizophrenia combined with GWAS data of the Han Chinese population and psychiatric genomics consortium.

ABSTRACT: Schizophrenia (SCZ) is a severe psychiatric disorder with evidence of a strong genetic component in the complex etiologies. Some studies indicated that gamma-aminobutyric acid (GABA)A receptor ?2 subunit gene (GABRB2) was associated with SCZ. Other studies reported a negative association. Moreover, the results of two previous meta-analyses of GABRB2 with SCZ were inconsistent and the sample sizes were limited. Therefore, an updated meta-analysis combined with genome-wide association study (GWAS) data of the Han Chinese population and Psychiatric Genomics Consortium (PGC) was performed. Available case-control and family-based genetic data were extracted from association studies, and the GWAS data were included. The findings showed no association between six single-nucleotide polymorphisms of GABRB2 (rs6556547, rs1816071, rs1816072, rs194072, rs252944, and rs187269) and SCZ in a total of 51,491 patients and 74,667 controls. The ethnic subgroup analysis revealed no significant association in Asian populations. Since the PGC data of SCZ (SCZ-PGC, 2014) contained 3 studies of Asian populations (1866 patients and 3418 controls), only the data of European samples in SCZ-PGC were used for the meta-analysis of the Caucasian population in the present study. The result still showed no association in the Caucasian population. In conclusion, the present meta-analysis on combined data from GWASs of the Han Chinese population and PGC suggested that GABRB2 polymorphisms might not be associated with SCZ.

PROVIDER: S-EPMC5997335 | BioStudies |

REPOSITORIES: biostudies

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Project description: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 ?2 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.

Project description:Genetic association studies on schizophrenia (SZ) have been repeatedly performed over the last two decades, resulting in a consensus that results are generally inconsistent. This consensus has begun to change as a result of meta-analyses (e.g., [Glatt, S.J. and Jonsson, E.G., 2006. The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, 149-154.]). The SchizophreniaGene database (http://www.schizophreniaforum.org/res/sczgene/default.asp) has been a leader in meta-analyses of SZ association data, by dynamically and comprehensively cataloging all public genetic association studies, and preparing meta-analyses of case-control data. There are 19 "top" candidate genes from these analyses (access on December 20, 2007), showing the highest effect sizes and nominally significant associations of at least one variant in the meta-analyses of all ethnic samples or of samples of Caucasian ancestry. We selected 40 polymorphisms in 12 selected "top" genes for additional meta-analyses, which had at least one familial association data. We found gene-wide (correction for the number of meta-analyses for each gene) significant allelic association evidence for seven genes in the combined samples. The odds ratios (ORs) of the associated minor risk alleles range from 1.072 to 1.121, for DRD4, MTHFR, PPP3CC and TP53. For protective allele associations, the ORs are between 0.842 and 0.886, for DAO, IL1B, and SLC6A4. In population-based sub-analyses, we found significant results in four genes in Asians (ORs between 1.084 and 1.309 for DRD4, GABRB2, PPP3CC, and TP53), and one gene in European (OR of 0.888 for SLC6A4). The association of rs1816072 of GABRB2 with SZ in Asians was significant (adjusted P=0.048 after correction for 80 tests). No significant heterogeneity between case-control and family-based study designs was detected in 35 out of 40 polymorphisms. Our results further support eight potential SZ candidate genes and suggest that family data can reasonably be included in the meta-analysis of genetic associations.

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Meta-analysis of GABRB2 polymorphisms and the risk of schizophrenia combined with GWAS data of the Han Chinese population and psychiatric genomics consortium.

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