Abstract
Mental Disorders (MDs) are multifactorial diseases and have heritability between 20% and 80%. This suggests that the genome contains a large amount of information with the potential to be used as a genetic risk marker for MDs. However, the polygenic nature of these diseases, added to the influence of dynamic environmental factors, makes it harder to investigate this information. The expansion of genomic studies on a large scale allowed the creation of a predictive tool called polygenic risk score (PRS). Two limitations of the PRSs are comprising only single nucleotide variants (SNVs), not considering larger variants such as Copy Number Variants (CNVs) and the decreased prediction in non-European populations, which adds a new level of difficulty to apply it to admixed population. As MDs are multifactorial diseases, longitudinal approaches are essential to understand how genetic risk interacts with dynamic and modifiable variables such as environmental factors. In neuroscience, one of the alternatives to gain access to brain tissue is through the evaluation of small extracellular vesicles that can carry nucleic acids and are capable of crossing the blood-brain barrier. The aims of this proposal are into two modules: 1) Genomic Module: aims to improve the PRS approaches already available for the admixed Brazilian population, apply local ancestry analysis to reassemble native Brazilian haplotypes, and use PRS combined with copy number variation (CNVs) as predictors for MDs in Brazilian cohorts; 2) Epigenomic Module: to evaluate the expression of miRNA in serum extracellular vesicles of individuals before and after the transition of MDs. This project will use two Brazilian cohorts: the BHRCS, which comprises 2500 families and has a >10-year follow-up, and PUMAS-Brasil, which will sequence 20,000 Brazilians in 5 cities. For the PRS analysis, we will use both BHRC and PUMAS-Brazil cohorts with a combined N of 25,000 genotype data. For the Epigenomic Module, we will use 500 samples from the BHRC, giving priority to individuals with longitudinal data and who converted or remitted MDs symptoms within a 10-year period. Isolation of extracellular vesicles as well as miRNA sequencing will be done according to protocols already standardized by the group. As the main scientific finding, we intend to 1) demonstrate the feasibility and an effective solution for the use of PRS in an admixed population and 2) identify miRNAs associated with the onset of mental disorders and 3) integrate the data from the two modules taking into account genetic factors and epigenetics that predispose to the transition of MDs. (AU)
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