Combined risk score for mental disorders considering single nucleotide variants (SNVs), Copy Number Variants (CNVs) and miRNA expression

• Grant number: 24/02453-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2024
• End date: March 31, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Marcos Leite Santoro
• Grantee: Júlia Arendt Antonieto
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 23/05560-6 - Genetic and epigenetic approaches as predictive models in mental disorders, AP.JP

Abstract

Psychiatric disorders are one of the main causes of years of life lost due to disability. Symptoms often begin during adolescence and can progress and persist into adulthood. As they are multifactorial phenotypes, environmental and genetic risk factors contribute to their establishment. Among genetic risk factors, common variants (SNVs) are currently the most used to predict the risk of mental disorders. However, in addition to SNVs, the heritability of these disorders can be explained by gene-gene, gene-environment interactions and also by other genetic variants such as copy number variants (CNVs). Recent studies in schizophrenia have demonstrated that the sum of common genetic factors measured by SNVs and CNVs can act simultaneously, increasing or decreasing the risk of developing the disease. Furthermore, the study of dynamic variables that can change over time are important for understanding why some individuals at genetic risk convert to psychiatric disorders and others do not. Therefore, the study of miRNAs from exosomes may play a role in the pathogenesis of these disorders and be related to the process of conversion or remission of symptoms. This project aims to build an integrated model for calculating the risk of mental disorders considering the joint impact of SNVs (using the polygenic risk score - PRS), CNVs and expression of miRNAs. Then, genotyping and miRNA expression data from 5,364 individuals from the Brazilian High-Risk Cohort Study (BHRCS) will be used, a longitudinal study that includes approximately 2,190 probands and 3,174 parents with already genotyped data. Regarding CNV data, we used PennCNV for detection, 14,304 CNVs were found in the entire cohort, 5,502 duplications and 8,783 deletions. To date, it has been possible to gather in the entire cohort the presence of CNVs that have already been associated with mental disorders in the literature, and may therefore be a risk factor for the development of these disorders. The goal of data integration can provide new insights into the process of conversion to mental disorders as well as identify people at high risk. The results obtained from this study may contribute in the future to new predictive models of individuals at risk, which in turn may allow interventions before the onset of psychiatric disorders in order to avoid the unfavorable course of these diseases.