The genetic architecture of cross-disorders within families: a multi-omic study of autism, bipolar disorder, and schizophrenia

• Grant number: 24/21129-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Maria Rita dos Santos e Passos Bueno
• Grantee: Claudia Ismania Samogy Costa
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BD), are complex conditions that share phenotypic and genetic traits, suggesting an overlapping etiology. Copy number variations (CNVs), common SNPs, and rare variants contribute to these cross-disorders risk by impacting genes in pathways such as those related to synaptic function, calcium channels, and GABA receptor signaling. The main hypothesis of this project is that ASD, SCZ and BD share genetic risk factors that sensitize the central nervous system (CNS) development and function, while additional risk variants act as modifiers, determining the phenotypic outcome of each individual. Notably, multiplex families with individuals affected by ASD and relatives with SCZ or BD provide a unique opportunity to explore overlapping genetic mechanisms and disorder-specific modifiers within shared genetic backgrounds. This study aims to investigate the role of de novo, rare, and common genetic variants in the manifestation of these neuropsychiatric conditions within multiplex families. We will study a minimum of 50 families (up to 70), totaling 300 individuals (including affected and unaffected individuals) with at least one ASD proband and a 1st or 2nd relative with SCZ or BD, in addition to healthy relatives. Our strategy combines Blended Genome Exome (BGE) sequencing with CRISPR screen assays and single-cell RNA sequencing (scRNA-Seq) to identify potential candidate genes and biological pathways, and to assess the functional impact of known associated genes and variants, through transcriptomic data. The BGE sequencing can capture multiple types of genetic variation-ranging from rare and common point mutations to CNVs- within a single experiment with a decreased overall cost, while CRISPR screening assays allow testing multiple risk genes (and their combinations) in parallel. We expect to establish a well-clinically defined sample and to identify both shared and disorder-specific candidate risk genes and biological pathways, which may act as CNS sensitizers and disorder modifiers, respectively. In addition, by selecting known associated genes/variants from each group (ASD-only, SCZ/BD-only and shared ones), we will use CRISPR screening assays to generate multiple hit mutant neurons containing diverse combinations of sensitizer and modifier genes. One pool of neurons will harbor combinations of mutations in shared (sensitizer) risk genes alongside ASD-specific risk genes (modifiers), while the other pool will combine the same sensitizers risk genes with SCZ/BD-specific modifiers. scRNA-Seq will then be performed to assess how the transcriptional profiles of neurons potentially diverge in response to these disorder-specific modifiers, despite the shared sensitizer mutations. Understanding these genetic factors may help refine diagnoses, improve genetic counseling, identify convergent pathways, and advance personalized treatment strategies.