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.
This research was carried out to quantify the duration from symptom onset to recovery/death (SOR/SOD) during the first four waves and the Alpha/Delta period of the epidemic in Khyber Pakhtunkhwa, Pakistan, and identify the associated factors. A total of 173,894 COVID-19 cases were admitted between 16 March 2020 and 30 November 2021, including 458 intensive care unit (ICU) cases. The results showed that the case fatality rate (CFR) increased with age, and females had a higher CFR. The median SOR of ICU cases was longer than that of non-ICU cases (27.6 vs. 17.0 days), while the median SOD was much shorter (6.9 vs. 8.4 days). The SOR and SOD in the Delta period were slightly shortened than the Alpha period. Age, cardiovascular diseases, chronic lung disease, diabetes, fever, breathing issues, and ICU admission were risk factors that were significantly associated with SOD (p < 0.001). A control measure, in-home quarantine, was found to be significantly associated with longer SOD (odds ratio = 9.49, p < 0.001). Infected vaccinated individuals had longer SOD than unvaccinated individuals, especially for cases that had received two vaccine doses (p < 0.001). Finally, an advice on getting full-dose vaccination is given specifically to individuals aged 20–59 years.
Premenstrual dysphoric disorder (PMDD) affects nearly 5% women of reproductive age. The symptomatic heterogeneity, along with largely unknown genetics, of PMDD have greatly hindered its effective treatment. In the present study, 127 Chinese PMDD patients of the 'invasion' and 'depression' subtypes clinically differentiated by us earlier were analyzed together with 108 non-PMDD controls for genome-wide copy number variations (CNVs). Germline genomic DNA samples from white blood cells were subjected to AluScan sequencing-based CNV profiling, which enabled clustering of patient samples readily into the V and D groups, dominated by the "invasion" and "depression" clinical subtypes, respectively; the CNVs obtained with 100-kb windows yielded two clusters that were correlated with these subtypes with a consistency of up to 89.8%. Diagnostic correlation- and frequency-based CNV features of either CNV-gain (CNVG) or CNV-loss (CNVL) that could differentiate between V and D subtypes were selected and analyzed. CNVG features located preferentially in S2-phase replicating regions and enriched with steroid hormone biosynthesis pathway of genes were found protective against PMDD. Moreover, machine learning employing the correlation-based CNV features could predict with >80% accuracy whether a genomic sample was D-type, V-type or control. In terms of their CNV profiles, the D- and V-types differed more from one another than from the controls, thereby providing a genomic basis for the clinical D-V subtyping of PMDD. Genome-wide profiling of CNVs, as a new approach to complex disease genetics, has revealed recurrent CNVs and genomic features beyond individual genes and mutations underlying PMDD clinical diversity.
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