Schizophrenia is a complex genetic disorder, the inheritance pattern of which is likely complicated by epigenetic factors yet to be elucidated. In the present study, single nucleotide polymorphisms (SNPs) in the GABA_A receptor β₂ subunit gene (GABRB2) were found to be associated with schizophrenia but not Alzheimer’s disease. In addition, transmission disequilibrium tests with family trios yielded significant differences between paternal and maternal transmissions of the schizophrenia-associated SNP rs6556547 and its haplotypes. The minor allele (T) of rs6556547 was paternally undertransmitted to male schizophrenic offsprings, and this parent-of-origin effect (POE) strongly suggested that GABRB2 is imprinted. ‘Flipping’ of allelic expression in heterozygotes of SNP rs2229944 (C/T) in G...[ Read more ]

Schizophrenia is a complex genetic disorder, the inheritance pattern of which is likely complicated by epigenetic factors yet to be elucidated. In the present study, single nucleotide polymorphisms (SNPs) in the GABA_A receptor β₂ subunit gene (GABRB2) were found to be associated with schizophrenia but not Alzheimer’s disease. In addition, transmission disequilibrium tests with family trios yielded significant differences between paternal and maternal transmissions of the schizophrenia-associated SNP rs6556547 and its haplotypes. The minor allele (T) of rs6556547 was paternally undertransmitted to male schizophrenic offsprings, and this parent-of-origin effect (POE) strongly suggested that GABRB2 is imprinted. ‘Flipping’ of allelic expression in heterozygotes of SNP rs2229944 (C/T) in GABRB2, or rs2290732 (G/A) in the neighbouring GABRA1 was compatible with imprinting effects on gene expression. Clustering analysis of GABRB2 mRNA expressions suggested that imprinting brought about the observed two-tiered distribution of expression levels in controls with heterozygous genotype at the schizophrenia-associated SNP rs1816071 (A/G). The deficit of upper-tiered expressions accounted for the lowered expression levels in the schizophrenic heterozygotes. The occurrence of a two-tiered distribution furnished support for imprinting, and also pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulphite sequencing revealed hyper-methylation in the neighbourhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, the two schizophrenia-associated SNPs rs6556547 and rs1816071 overlapped with a CpG dinucleotide, thereby opening the possibility that CpG methylation status of these sites could modulate the risk of schizophrenia. Thus multiple lines of evidence pointed to the occurrence of imprinting in the GABRB2 gene and its possible role in the development of schizophrenia.