Schizophrenia is a heritable disorder with common variants contributing up to 50 percent of its genetic variance. The study by Reese et al. (2019) sought to establish that multiple voltage-gated sodium channels form a significant aspect in schizophrenic pathogenesis.
The Major Questions the Authors were Asking
The authors of this study establish that schizophrenia is involved in the rare coding of N-methyl-D-aspartate receptor (NMDAR) and activity-regulated cytoskeleton-associated protein (ARC) complexes. While this is the case, there is a need for using large samples of schizophrenic genes to understand the specific biological mechanisms and novel genes. The authors wanted to establish the role of rare exonic variants in the NMDAR and ARC synaptic complexes. These synaptic complexes are considered as significant risk factors for schizophrenia. In the same manner, the authors wanted to understand the connection between the alpha subunits of voltage-gated sodium channels and NMDAR and ARC missense and loss-of-function variants. The authors' primary aims were to test the schizophrenic genes for the enrichment of rare coding variants (RCVs). Moreover, the authors wanted to understand if the genes implicated in schizophrenia had rare coding variants. Additionally, the researchers hoped to identify the specific schizophrenic genes that are enriched with the rare coding variants.
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The authors base their question son prior research studies that implicate loss-of-function (LoF) variants as significant contributors to schizophrenia pathogenesis. In this study, the researchers wanted to establish that missense variant also increase the risk of schizophrenia. However, it is essential to note that while missense variants contribute to schizophrenia, silico methods cannot distinguish between benign missense and variants that alter encodedproteins' function. In this case, the authors hoped to come up with ways of identifying pathogenic variants and, in this way, understand paralogous gene families.
The Key Findings from the Research
The research study involved 11,493 blood-derived DNA samples that had been targeted for sequencing. It is important to note that none of the samples had been included in past schizophrenia sequencing studies meaning that the results would be unique. Out of the sample, the research team picked several genes and coded them into four gene sets. The four sets are NMDAR ( n = 61 ), ARC ( n = 28 ), voltage-gated sodium channels (n = 14) and voltage-gated calcium channels (n = 26) (Reese et al., 2019). Moreover, the team sequenced an additional 58 genes, which are associated with schizophrenia. From here, the researchers conducted six burden tests to confirm the enrichment of RCVs in the 187 genes. The six burden tests indicated an excess of LoF mutations, which was concentrated in genes that are known to be intolerant to LoF. Furthermore, the results indicated that there was a greater association between rare LoF variants and schizophrenia in the LoF- intolerant genes. The research team found out that there was an enrichment of RCVs for LoF variants found in voltage-gated sodium channels. However, the researchers did not find any evidence that links schizophrenia to voltage-gated calcium channels.
The research findings indicated an excess of paralog-conserved missense and LoF in the sodium channels, but the variants were not found in the calcium channels. The researchers had separated the genes into two functional groups, beta and alpha to understand the linkage between voltage-gated sodium channel. The findings indicate that only the alpha genes are enriched with the paralog-conserved missense and LoF variants. In the same manner, the research findings suggest that ARC has higher rates of LoF variants as compared to NMDAR, but those in the NMDAR complex are associated with schizophrenia. When the team combined the meta-analysis data with the de novo variant data, they established that both NMDAR and ARC complexes are associated with schizophrenia. To this end, NMDAR and ARC complexes share up tp nine overlapping genes.
How the Article is Biologically Relevant And How It is related To Class
The research study that indicates that voltage-gated sodium channels in schizophrenia pathogenesis is biologically relevant for various reasons. This research revolving around sequencing studies provides excellent insights into the etiology and architecture of schizophrenia. The identification of excess in Loss-of Function (LoF) variants in genetic samples forms the basis for understanding the dynamics of schizophrenia. The study is relevant, considering that it helps to link sodium channels variants to neurodevelopmental disorders such as delay in development and epilepsy (Reese et al., 2019). These findings are crucial as they indicate that there is a strong correlation between schizophrenia and these neurodevelopmental disorders. In the same manner, the association between schizophrenia and the RCVs in the sodium channels indicates increased risk for schizophrenia. The research could be used to determine one's susceptibility to schizophrenia from an early stage and probably reduce its adverse effects.
The research study is related to the class in more than one way considering that it focuses on sodium and calcium leak channels. The research study indicates that the sodium channel, which contains ten alpha units and four beta subunits, modulate cellular excitability and gating. The nature of the sodium channel is a significant contributor to schizophrenia pathogenesis since it is a protein-coding region. This study is vital considering that it brings an entirely new understanding into the issue of allele frequencies, a part of the leak channels. LoF-intolerant genes contribute to deep phenotyping of schizophrenic risk variants, which in turn increase one's susceptibility to schizophrenia. In the same manner, rare coding variants (RCVs) found in the sodium leak channels point to a higher risk for schizophrenia. To this end, the study contributes to the biological discourse and, more specifically, brings about a new understanding of schizophrenia. Further research into sodium-channel genes that are responsible for schizophrenia and neurodevelopmental disorders would compound these findings.
Reference
Rees, E., Carrera, N., Morgan, J., Hambridge, K., … & Escott-Price, V. (2019). Targeted sequencing of 10,198 samples confirms abnormalities in neuronal activity and implicates voltage-gated sodium channels in schizophrenia pathogenesis. Biological Psychiatry , 85(7), 554–562. https://doi.org/10.1016/j.biopsych.2018.08.022
