Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA A receptor Β2 subunit

Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Molecular Psychiatry (Impact Factor: 14.5). 05/2011; 16(5):557-68. DOI: 10.1038/mp.2010.47
Source: PubMed


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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    • "Epigenetic alterations can reflect the interaction between genetic factors and environmental ones in the development of SCZ [Abdolmaleky and Thiagalingam, 2011]. As the major component of epigenetic regulation, DNA methylation of GAD, RELN, COMT, SOX10, BDNF, and CTLA4 genes have been reported to be correlated with the risk of SCZ [Abdolmaleky et al., 2005, 2006; Abdolmaleky and Thiagalingam, 2011; Grayson et al., 2005; Ikegame et al., 2013; Iwamoto et al., 2005; Kordi-Tamandani et al., 2013; Nohesara et al., 2011; Pun et al., 2011; Sharma et al., 2008; Tolosa et al., 2010]. SCZ is a complex mixed disorder with two major subtypes, paranoid and undifferentiated SCZ. "
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    ABSTRACT: Schizophrenia (SCZ) is a complex mental disorder contributed by both genetic and epigenetic factors. Long noncoding RNAs (lncRNAs) was recently found playing an important regulatory role in mental disorders. However, little was known about the DNA methylation of lncRNAs, although numerous SCZ studies have been performed on genetic polymorphisms or epigenetic marks in protein coding genes. We presented a comprehensive genome wide DNA methylation study of both protein coding genes and lncRNAs in female patients with paranoid and undifferentiated SCZ. Using the methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), 8,163 and 764 peaks were identified in paranoid and undifferentiated SCZ, respectively (p < 1×10-5). Gene ontology analysis showed that the hypermethylated regions were enriched in the genes related to neuron system and brain for both paranoid and undifferentiated SCZ (p < 0.05). Among these peaks, 121 peaks were located in gene promoter regions that might affect gene expression and influence the SCZ related pathways. Interestingly, DNA methylation of 136 and 23 known lncRNAs in Refseq database were identified in paranoid and undifferentiated SCZ, respectively. In addition, ∼20% of intergenic peaks annotated based on Refseq genes were overlapped with lncRNAs in UCSC and gencode databases. In order to show the results well for most biological researchers, we created an online database to display and visualize the information of DNA methyation peaks in both types of SCZ ( Our results showed that the aberrant DNA methylation of lncRNAs might be another important epigenetic factor for SCZ. Copyright © 2014. Published by Elsevier Masson SAS.
    Full-text · Article · Dec 2014 · European Journal of Medical Genetics
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    • "Contribution of GABRB2 to SCZ etiology was further supported by the differential expression of different splicing variants of the gene in SCZ patients relative to control subjects [10], [11]. Recently, evidence for imprinting of GABRB2 was revealed [12], supporting the involvement of genomic imprinting in the development of SCZ [13]. That the disorder persists in the face of its reproductive disadvantage poses an apparent evolutionary paradox [14], and the findings of co-occurrence of recombination and positive selection in this region of GABRB2 [15], [16] has shed some insight into potential genetic mechanisms underlying the phenomenon. "
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    ABSTRACT: The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "They also reported hypermethylation of S-COMT (which encodes the soluble form of COMT) and no differential methylation of SLC6A4 in peripheral blood cells derived from schizophrenia patients. Other groups have reported hypermethylation of the promoter region of 5HTR1A (which encodes serotonin receptor 1A) in leukocytes [70], and hypermethylation of the region around the schizophrenia-associated SNP (rs1816071) of GABRB2 (which encodes the β2 subunit of GABA(A) receptor) in leukocytes [71]. Further studies will be needed to understand the patterns of DNA methylation in leukocytes from schizophrenia patients. "
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    ABSTRACT: Schizophrenia is a severe psychiatric disease affecting about 1% of the world's population, with significant effects on patients and society. Genetic studies have identified several candidate risk genes or genomic regions for schizophrenia, and epidemiological studies have revealed several environmental risk factors. However, the etiology of schizophrenia still remains largely unknown. Epigenetic mechanisms such as DNA methylation and histone modifications can explain the interaction between genetic and environmental factors at the molecular level, and accumulating evidence suggests that such epigenetic alterations are involved in the pathophysiology of schizophrenia. However, replication studies to validate previous findings and investigations of the causality of epigenetic alterations in schizophrenia are needed. Here, we review epigenetic studies of schizophrenia patients using postmortem brains or peripheral tissues, focusing mainly on DNA methylation. We also highlight the recent progress and challenges in characterizing the potentially complex and dynamic patterns of epigenomic variations. Such studies are expected to contribute to our understanding of schizophrenia etiology and should provide novel opportunities for the development of therapeutic drugs.
    Preview · Article · Dec 2012 · Genome Medicine
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