Characterization of LINE-1 genomic regions in subjects from a high-risk community cohort for psychiatric conditions

• Grant number: 24/15037-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2024
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Síntia Iole Nogueira Belangero
• Grantee: Sabrina Torres Loureiro
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 21/05332-8 - Brazilian high-risk cohort for psychiatric disorders: 10 years follow-up, AP.TEM

Abstract

Advances in molecular and diagnostic techniques have improved our understanding of the etiology of psychiatric conditions, but the diagnosis and management of individuals with psychiatric conditions remains a major challenge. From a biological point of view, psychiatric disorders have a considerable genetic component, with heritability ranging from 0.37 to 0.85, depending on the disorder, which means that 37% to 85% of the etiology of mental disorders can be attributed to genetic factors. In this sense, genome wide association studies (GWAS) have played a crucial role in understanding the genetic basis of these disorders. However, these studies have mainly focused on common genetic variations, for example, single nucleotide variants (SNVs), which have a small effect on the risk of mental disorders. It is believed that the rest of the heritability can be explained by gene-gene, gene-environment interaction and also by other genetic variants that do not make up the heritability of SNVs such as mobile elements (e.g. LINE-1, SINE-R and Alu regions). Whole genome sequencing (WGS) has emerged as a promising tool for identifying these variants and allows for a better understanding of the genetic basis of psychiatric conditions, since the WGS method has high coverage and has the potential to identify rare variants in approximately 99% of the non-coding genome, such as CNVs or retrotransposons.LINE-1 are a type of retrotransposon, which make up around 17% of the human genome and are mobile elements, i.e. they have the ability to move around the genome by means of a "copy and paste" mechanism; in previous studies, the presence of these genomic regions has been associated with genomic instability and an increase in the number of copies of these specific sequences has already been found in individuals diagnosed with severe mental disorders such as schizophrenia.Thus, this study aims to verify the impact of LINE-1 on psychopathology, individual functionalities, severity and symptoms presented.To this end, we will analyze 2311 whole genomes (WGS) of young people from the Brazilian high-risk cohort (BHRCs) for mental disorders and their respective clinical data. The WGS was carried out at 30X coverage on the Illumina platform. We will use the MELT (Mobile element locator tool), TEbreak and xTEA tools to find the positions of the LINE-1 insertions, from which we will establish whether they are coding or regulatory regions in the DNAs of the individuals. All the analyses will be carried out in the command line and in the R environment. We will then carry out appropriate statistical tests to compare the groups or carry out regressions and other statistical models. We hope to find an association between the number and location of mobile elements and clinical-psychiatric findings, thus increasing knowledge of the neurobiology and pathophysiology of mental conditions. (AU)