Complex diseases such as schizophrenia (SCZ) represent the results of the interaction between multiple factors including genetic and environmental influences and account for the leading causes of mortality in the world. By investigating the genetic components of the etiology of complex diseases, one can gain a better understanding of the biological pathways underlying complex diseases and the heterogeneity of risk factors. The recent advances in whole-genome sequencing (WGS) and the availability of genome-wide association study (GWAS) data have enabled researchers to explore and assess these complex diseases. Accordingly, I have sought to investigate some of the complex traits and diseases using established as well as novel genomic technologies, including whole-genome and transcriptome...[ Read more ]

Complex diseases such as schizophrenia (SCZ) represent the results of the interaction between multiple factors including genetic and environmental influences and account for the leading causes of mortality in the world. By investigating the genetic components of the etiology of complex diseases, one can gain a better understanding of the biological pathways underlying complex diseases and the heterogeneity of risk factors. The recent advances in whole-genome sequencing (WGS) and the availability of genome-wide association study (GWAS) data have enabled researchers to explore and assess these complex diseases. Accordingly, I have sought to investigate some of the complex traits and diseases using established as well as novel genomic technologies, including whole-genome and transcriptome sequencing. The GABRB2 gene encoding the GABA_A receptors beta-2 subunit is known to be involved in different psychiatric disorders such as SCZ. Our recent findings included the display of schizophrenia-like and comorbid phenotypes by Gabrb2 knockout mice. To find the pathways and genes underlying these phenotypes, whole transcriptome analysis was conducted for the Gabrb2 knockout mice. Using the wildtype as control, Gabrb2 knockout mice showed an altered expression of several genes that are linked to different aspects of SCZ, such as deficit in intracellular trafficking of GABA_A receptors, disruption in adult neurogenesis, excitotoxicity, and neuroinflammation.

Previously, single nucleotide polymorphisms in GABRB2 were found to be associated with SCZ, but it is unknown whether there is any association of Copy Number Variation (CNVs) in this gene with either SCZ or the premenstrual dysphoric disorder (PMDD) which is known to cause anxiety. Accordingly, 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 investigated. The results demonstrated that copy-number-gains were enriched in both SCZ and PMDD cases with significant odds ratios (OR). Next, we performed AluScan sequencing of 127 PMDD samples. Based on the CNV profiling of each genome, the PMDD patients could be clustered into two major subgroups that are highly correlated with the clinical distinction between the depression-type versus the invasion-type of this disease.

Apart from maintaining normal function of the nervous system by binding with GABA, the GABA_A receptors are also major targets for drugs associated with neuropsychiatric disorders. There is a lack of high-resolution studies of these receptors, particularly on the structural elements related to its channel activation mechanism and allosteric modulations. In view of this, we have prepared protein samples of the α1, β2, and γ2 subunits of GABA_A receptors for structural analysis. The results from electron microscopy showed that these recombinant proteins formed rosette-like homo-oligomers, mainly pentamers, and these subunits remained biologically active, sharing similar secondary structural contents. Therefore, their fragments apparently provide a valuable model system for studying the pentameric holoreceptor assembly that could lead to a high-resolution atomic structure for an important family of neurotransmitter receptors pivotal in SCZ and comorbid disorders, thereby paving the way to new therapeutics for neuropsychiatric diseases.