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Imprinting in the schizophrenia candidate gene GABRB2 encoding GABAA receptor β2 subunit

Abstract

Schizophrenia is a complex genetic disorder, the inheritance pattern of which is likely complicated by epigenetic factors yet to be elucidated. In this study, transmission disequilibrium tests with family trios yielded significant differences between paternal and maternal transmissions of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 and its haplotypes. The minor allele (T) of rs6556547 was paternally undertransmitted to male schizophrenic offsprings, and this parent-of-origin effect 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 neighboring 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 disease-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. Bisulfite sequencing revealed hypermethylation in the neighborhood 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 have an impact on 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.

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Acknowledgements

We are grateful to the Fok Ying Tung Foundation for their generous donation, and the University Grants Council and the Innovation and Technology Fund of Hong Kong SAR Government and Guangdong Natural Science Foundation for financial support. We thank Ms Peggy Lee and Mr Wai Lee for their valuable assistance. We also thank the Stanley Medical Research Foundation, Hong Kong Red Cross, Hong Kong Tai Po Hospital, Sha Tin Hospital and Prince of Wales Hospital for allowing their patients to participate in the study.

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Pun, F., Zhao, C., Lo, WS. et al. Imprinting in the schizophrenia candidate gene GABRB2 encoding GABAA receptor β2 subunit. Mol Psychiatry 16, 557–568 (2011). https://doi.org/10.1038/mp.2010.47

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