Summary
This project aims to characterize the causal mechanisms of schizophrenia by studying rare variants in the SETD1A gene within the Old Order Amish population, utilizing cognitive, psychiatric, cellular, and neurodevelopmental phenotyping, and single-cell multi-omic technologies.
What they want
The project proposes three main experimental phases: 1) Recruit 128 Amish carriers of SETD1A variants and their blood relatives to ascertain deep cognitive and psychiatric symptom phenotypes, testing hypotheses regarding allelic heterogeneity, allele frequency dependence, dose dependence, and interactions with polygenic risk. 2) Obtain induced pluripotent stem cells (iPSCs) from a subset of these individuals to identify cellular and neurodevelopmental phenotypes, characterize allelic heterogeneity at a cellular level, and test if cellular phenotypes can be rescued by restoring H3K4me3 levels. 3) Test the hypothesis that SETD1A variants alter the chromatin potential of developing neurons using single-cell multi-omic technologies and network modeling techniques.
Deliverables
- Deep cognitive and psychiatric symptom phenotypes for SETD1A variant carriers
- Characterization of allelic heterogeneity, allele frequency dependence, dose dependence, and polygenic risk interactions related to SETD1A variants
- Identification of cellular and neurodevelopmental phenotypes from iPSCs of SETD1A variant carriers
- Characterization of allelic heterogeneity at a cellular level
- Results on the rescue of cellular phenotypes by restoring H3K4me3 levels
- Findings on how SETD1A variants alter the chromatin potential of developing neurons
Technical requirements
- Deep cognitive and psychiatric symptom phenotyping
- Induced pluripotent stem cell (iPSC) generation and analysis
- Single-cell multi-omic technologies
- Network modeling techniques
