Discovery of rare variants implicated in schizophrenia using next-generation sequencing

Abstract

Schizophrenia is a highly heritable psychiatric disorder that affects 1% of the population. Genome-wide association studies have identified common variants in candidate genes associated with schizophrenia, but the genetics mechanisms of this disorder have not yet been elucidated. The discovery of rare genetic variants that contribute to schizophrenia symptoms promises to help explain the missing heritability of the disease. Next generation sequencing techniques are revolutionizing the field of psychiatric genetics. Various statistical approaches have been developed for rare variant association testing in case-control and family studies. Targeted resequencing, whole exome sequencing and whole genome sequencing combined with these computational tools are used for the discovery of rare genetic variations in schizophrenia. The findings provide useful information for characterizing the rare mutations and elucidating the genetic mechanisms by which the variants cause schizophrenia.

Disruption of Alternative Splicing in the Amygdala of Pigs Exposed to Maternal Immune Activation

“…SHANK1 mRNA is expressed predominately in the cerebral cortex, hippocampus, and amygdala and an isoform survey included SHANK1B (lacking the C-terminal SAM domain), SHANK1C (lacking the N-terminal ankyrin repeat domain), and SHANK1D (lacking the ankyrin repeat domain, and SH3 or SAM domains) [68]. The most extreme MEGF8 isoform was under-expressed (8.7%) in MIA relative to control weaned females, and this finding could be correlated with reports of gene variants associated with SSD [69].…”

Current progress in understanding Schizophrenia using genomics and pluripotent stem cells: A Meta-analytical overview

“…Over the last decade, GWAS has revolutionized the field of complex genetic diseases such as SCZ, by massively genotyping large sample sizes of patients to find genotype-phenotype relationships (Schizophrenia Working Group of the Psychiatric Genomics 2014; Uffelmann et al 2021). GWAS and NGS have helped in capturing genetic variants, which constitute to partially reveal SCZ genetics (Rhoades, Jackson, and Teng 2019).…”

“…However, the discovery of common genetic variants in SCZ has only provided insights into a fraction of SCZ genetics and fuelled a debate about the missing heritability in complex diseases (van Dongen and Boomsma 2013; Zuk et al 2012; Maher 2008). This has also led to the hypothesis of the presence of undiscovered rare variants with high penetrance (Rhoades, Jackson, and Teng 2019).…”

“…The lack of discovery of causal genes by GWAS in SCZ makes the study of gene expression pertinent (Rhoades, Jackson, and Teng 2019; Stern, Zhang, et al 2022). Technological advancements in RNA sequencing have replaced the incomprehensive microarrays-based gene expression assays and allowed for the study of the whole transcriptome of the cells and tissues.…”

“…Schizophrenia (SCZ) is a complex neurological disease that manifests mainly in adulthood although reported to have a neurodevelopment origin (Bloom 1993; Fatemi and Folsom 2009; Ahmad et al 2018; Schultz, North, and Shields 2007). According to the WHO report, globally approximately 24 million people are affected with SCZ with a worldwide prevalence of around 1% (Stilo and Murray 2010; Rhoades, Jackson, and Teng 2019). SCZ patients are more likely to die younger than the general population mainly due to co-morbid conditions like cardiovascular, diabetes and communicable diseases (Wildgust, Hodgson, and Beary 2010).…”