Parent-child trio sequencing study of early-onset schizophrenia

• Grant number: 24/15006-9
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: September 01, 2024
• End date: August 31, 2025
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Agreement: CNPq
• Principal Investigator: Guilherme Vanoni Polanczyk
• Grantee: Luis Carlos Farhat
• Host Institution: Instituto de Psiquiatria Doutor Antonio Carlos Pacheco e Silva (IPq). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 24/02150-4 - Parent-child trio sequencing study of early-onset Schizophrenia, AP.R

Abstract

Importance: Our limited understanding of the neurobiological processes underlying schizophrenia has contributed to stalling the development of new treatments. The identification of genes associated with schizophrenia through the examination of rare variants is considered a promising approach to uncovering new pathophysiological processes and therapeutic targets. SCHEMA identified 32 risk genes by analyzing whole-exome data from thousands of individuals and parent-child trios with schizophrenia. However, in autism, twice the number of risk genes have been identified with twice the number of parent-child trios. Thus, we need to sequence more schizophrenia parent-child trios. Greater advancements will likely occur if we focus on extreme phenotypes such as early-onset (< 18 years) schizophrenia (EOS). Objective: To characterize the role of spontaneous (de novo) sequence and structural variation in EOS through sequencing of parent-offspring trios. Methods: We will recruit 40 parent-offspring trios in which the offspring has a diagnosis of schizophrenia and a definitive onset in childhood or adolescence (age < 18 years). We will collect saliva samples from each trio member and extract and store the DNA at the Biosciences Institute from the University of São Paulo (IBUSP). We will perform genome or whole exome sequencing. We will identify rare sequence and structural variants. For the analyses, we will focus on de novo variants. We will compare mutation rates in EOS with mutation rates in autism and typically developing controls from the Simons Simplex Collection. Hypothesis: We hypothesize that the rates of de novo damaging (i.e., protein truncating variants and missense predicted damaging variants) and de novo copy number variation in EOS will be similar to those rates in autism and greater than those in typically developing controls. Relevance: We will use this pilot study to support new funding applications in 2024 to conduct a large-scale study with an additional 220 trios. The study of 250 parent-offspring trios will have substantial potential to advance our knowledge about the genetics of EOS and schizophrenia. (AU)