Autism Spectrum Disorder: Genetic Architecture, Pathophysiological Mechanisms, and Diagnostic and Prognostic Tools.

• Grant number: 24/21989-5
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2025
• End date: September 30, 2030
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Maria Rita dos Santos e Passos Bueno
• Grantee: Maria Rita dos Santos e Passos Bueno
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Andréa Laurato Sertié ; Helena Paula Brentani
• Associated researchers: Ana Cristina Victorino Krepischi ; Ariane Machado Lima ; Débora Romeo Bertola ; Diego Luiz Rovaris ; Elizabeth Shephard ; Fabio Papes ; Fátima de Lourdes dos Santos Nunes Marques ; Gerson Shigeru Kobayashi ; Guilherme Lopes Yamamoto ; Guilherme Vanoni Polanczyk ; Karina Griesi Oliveira ; Mayana Zatz

Abstract

The Autism Spectrum Disorder (ASD) is a multifactorial neurodevelopmental disorder with a global prevalence of 1-2%, representing a significant public health challenge. Genetic studies highlight the complexity of ASD's genetic architecture and its importance for understanding clinical heterogeneity, pathophysiological mechanisms, and for the development of diagnostic biomarkers and personalized therapies. This project integrates three complementary axes to investigate ASD: (1) the underlying genetic architecture, (2) the pathophysiological mechanisms of genetic variants, and (3) the clinical heterogeneity and life-course trajectories. The integrative approach connects genetic, molecular, cellular, and clinical data, providing a deeper understanding of the factors shaping ASD. Axis 1 focuses on the genetic architecture of ASD, analyzing the interaction between rare and common variants and their relationship with phenotypic variability (differences in how the disorder manifests). A pipeline will be developed to evaluate the portability of Polygenic Risk Scores (PRSs) constructed in diverse populations to the Brazilian population, with a focus on selecting appropriate metrics for this population. Genetic homogenization models and family aggregation will also be explored to identify variants impacting phenotypic expressivity. Axis 2 investigates how genetic risk variants affect the cellular composition of the developing cerebral cortex, increasing vulnerability to neurodegenerative processes, particularly under the influence of inflammatory factors. Brain organoids (brain-like structures developed from stem cells) will be generated from induced pluripotent stem cells (iPSCs) derived from patients with pathogenic variants to study the predisposition to neurodegenerative phenotypes. Additionally, chimeric organoids, composed of cells from multiple donors, will be used to study variations in brain development and responses to environmental stressors. Axis 3 seeks to identify markers and tools to improve ASD diagnosis and prognosis, considering genetic architecture, clinical heterogeneity, and life-course trajectories. Various approaches will be applied, including computational tools and machine learning, to integrate genetic, clinical, neurophysiological, and epigenetic data, creating models for diagnosis, subgroup identification, and clinical follow-up. By adopting a holistic approach, the three axes of this project aim to deepen the understanding of the genetic and phenotypic complexity of ASD, its molecular mechanisms, with the expectation of generating results applicable to clinical practice and contributing to more precise diagnoses and personalized therapies. (AU)