Multiomic approaches: exploring genetic and epigenetic contributions to an oligogenic model of Autism Spectrum Disorder

• Grant number: 25/22859-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: April 15, 2026
• End date: March 26, 2027
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Maria Rita dos Santos e Passos Bueno
• Grantee: Gabriele da Silva Campos
• Supervisor: Evan Eichler
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Washington, United States
• Associated to the scholarship: 23/01887-0 - Investigation of epigenetic mechanisms in the etiology of Autism Spectrum Disorder in dystrophinopathies, BP.DD

Abstract

Autism Spectrum Disorder (ASD) is a complex neuropsychiatric condition with high heritability, yet its genetic architecture remains largely unelucidated. While monogenic models account for 10-20% of cases, evidence suggests that oligogenic and multifactorial models are essential for understanding ASD etiology. Our research line proposes an oligogenic model in the context of dystrophinopathies, a subgroup that presents an increased frequency of ASD compared to the general population. In this model, pathogenic variants in the DMD gene would act as a primary hit, predisposing individuals to neurodevelopmental alterations. Additional hits, represented by rare risk variants in genes related to the extracellular matrix (ECM) and collagen, would be critical for the manifestation of ASD, demonstrating the relevance of alterations in this pathway to neurodevelopment. To test this hypothesis, this proposal integrates two complementary objectives: i) a large-scale bioinformatics analysis to investigate the co-occurrence of variants in ECM and collagen genes in a cohort of 60,000 individuals with ASD, assessing the model's relevance in a broader sample; and ii) a genomic and epigenomic characterization of individuals with dystrophinopathies (EPIGEN-DMD sample) using long-read sequencing on the Oxford Nanopore Technologies (ONT) platform. This approach allows for the simultaneous analysis of the full spectrum of genetic variation (from SNVs to complex structural variants) and epigenetic modifications (such as DNA methylation) from a single assay. This research is expected to reveal new genetic and epigenetic risk factors for ASD and validate a context-specific oligogenic model. Additionally, the project will facilitate knowledge transfer in the analysis of long-read sequencing data to the genomic research community in Brazil, promoting training in bioinformatics and strengthening international scientific collaboration.