Using Rare Proteins to Measure Schizophrenia Risk
Over twenty-one million people or about 1% of people worldwide are affected by Schizophrenia. This disease stems from a variety of causes and involves structural alterations within the brain. These causes can be genetic and environmental, which together are referred to as genetic architecture.
Genetic architecture involves rules that govern how the genes of the organism (genotypes) relate to the expression of those traits (phenotypes). Some genes can directly relate to expressed traits, for example, if you have the dominant MC1R gene, you will have freckles. Meanwhile, other genes can, in combination, influence the expression of certain traits. In schizophrenia specifically, there are several levels of contribution to its genetic architecture. These levels include single-nucleotide polymorphisms, which will be referred to as SNPs, large copy number variants, or CNVs, and rare PTVs, or protein-truncating variants.
The most common of the above genetic architecture components, SNPs involve a modification of noncoding RNA and alterations of gene expression. Accordingly, this alteration changes structure and function at the level of gene expression. This modification occurs to one specific nucleotide, thus occurring often, in every 1,000 nucleotides. Specific SNP variants have been linked to Schizophrenia and are found in at least 1% of the population. Overall, SNPs have much smaller effects on Schizophrenia heritability, but they still explain 24% of the genetic and environmental factors that contribute to the disorder.
CNVs are much larger alterations than SNPs, as they affect thousands or more DNA bases. CNVs can either be deletions or duplications of these large chunks of DNA. A total of 8 CNVs have been linked to Schizophrenia, with an additional 2 implicated as likely being linked. People diagnosed with Schizophrenia on average carry 11% more CNVs than control populations.
PTVs are believed to be genetic variants that shorten the coding sequence within genes through DNA shorting. They are a subcategory of truncating variants, which refers to a shorter protein being produced, and frameshift mutations, which involve the deletion or insertion of nucleotides such that the DNA reading frame is shifted.
These PTVs allow for direct linkage of disease risk to individuals through at least 10 highly specific genes. People with any of these 10 PTVs are significantly more likely to develop Schizophrenia during their lifetime. This study proved that the implication of these 10 PTVs holds across 5 different ancestral populations and implicated two additional schizophrenia risk genes. It further discovered an additional gene shared between individuals affected with schizophrenia and with autism.
This study demonstrated how PVTs have a significant correlation to schizophrenia through genetic analysis of the entire human genome. This study of the genetic architecture hopes to lead to diagnostic testing for schizophrenia, as currently no diagnostic test or biomarkers for schizophrenia exists. The discussed discoveries have involved whole genome analysis, which is costly and impractical to use as diagnostic testing. In addition, an improved understanding of the genetics that lead to schizophrenia will hopefully allow for more specific treatment options for schizophrenia soon.
Bibliography:
Legge, S., Santoro, M., Periyasamy, S., Okewole, A., Arsalan, A., & Kowalec, K. (2021). Genetic architecture of schizophrenia: A review of major advancements. Psychological Medicine, 51(13), 2168–2177. doi:10.1017/S0033291720005334
Liu, D., Meyer, D., Fennessy, B. et al. Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations. Nat Genet 55, 369–376 (2023). https://doi.org/10.1038/s41588-023-01305-1
Marshall, C., Howrigan, D., Merico, D. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet 49, 27–35 (2017). https://doi.org/10.1038/ng.3725
