Objective Although single-nucleotide polymorphisms in GABRB2 , the gene encoding for GABA A receptors β2 subunit, have been associated with schizophrenia (SCZ), it is unknown whether there is any association of copy number variations (CNVs) in this gene with either SCZ or premenstrual dysphoric disorder (PMDD). Methods In this study, the occurrences of the recurrent CNVs esv2730987 in Intron 6 and nsv1177513 in Exon 11 of GABRB2 in Chinese and German SCZ, and Chinese PMDD patients were compared to controls of same ethnicity and gender by quantitative PCR (qPCR). Results The results demonstrated that copy-number-gains were enriched in both SCZ and PMDD patients with significant odds ratios (OR). For combined-gender SCZ patients versus controls, about two-fold increases were observed in both ethnic groups at both esv2730987 (OR = 2.15, p = 5.32E−4 in Chinese group; OR = 2.79, p = 8.84E−3 in German group) and nsv1177513 (OR = 3.29, p = 1.28E−11 in Chinese group; OR = 2.44, p = 6.17E−5 in German group). The most significant copy-number-gains were observed in Chinese females at nsv1177513 (OR = 3.41), and German females at esv2730987 (OR=3.96). Copy-number-gains were also enriched in Chinese PMDD patients versus controls at esv2730987 (OR = 10.53, p = 4.34E−26) and nsv1177513 (OR = 2.39, p = 3.19E−5). Conclusion These findings established for the first time the association of highly recurrent CNVs with SCZ and PMDD, suggesting the presence of an overlapping genetic basis with shared biomarkers for these two common psychiatric disorders.
The usage of next-generation sequencing (NGS) to detect copy number variation (CNV) is widely accepted in cancer research. Based on an AluScanCNV software developed by us previously, an AluScanCNV2 software has been developed in the present study as an R package that performs CNV detection from NGS data obtained through AluScan, whole-genome sequencing or other targeted NGS platforms. Its applications would include the expedited usage of somatic CNVs for cancer subtyping, and usage of recurrent germline CNVs to perform machine learning-assisted prediction of a test subject's susceptibility to cancer.
Background: The inhibitory GABAergic system has shown an association with multiple psychiatric disorders. The type A GABA receptors are an integral component of this system, and in recent years, evidence has accumulated to support an essential role in disease etiology for one of the receptor genes GABRB2 which encodes for the receptor β2 subunit. Objective: To summarize the different lines of evidence supporting the important role of GABRB2 in psychiatric disorders, with a particular focus on schizophrenia, and evaluate the recently-proposed GABRB2-origin of schizophrenia hypothesis. Results: In terms of genetics, Single Nucleotide Polymorphisms (SNPs) in GABRB2 have been associated with a number of psychiatric disorders, and some of the associations have remained significant following meta-analysis. Importantly, expression and alternative splicing of the gene was shown to be dependent on the genotypes of the associated SNPs, and receptors containing the long isoform displayed functional differences compared to those containing the short isoform. Moreover, differential epigenetic regulation and imprinting imbalance of the gene were observed in schizophrenic patients compared to healthy subjects. Finally, recent findings from a Gabrb2-knockout mouse model demonstrated that knockout of the gene alone was sufficient to induce a wide range of schizophrenia- like symptoms and comorbid phenotypes. Conclusion: The different lines of evidence coalesce to strongly support the recentlyproposed GABRB2-origin of schizophrenia hypothesis, and GABRB2 may also have a potential role in cognition, the dysfunction of which is common to many psychiatric disorders.
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