Probing Gene-environment Interactions in Schizophrenia and Stress: Integrating human GWAS and mouse models

2020 Award: $60,000

Schizophrenia is a heritable disorder that is impacted by environmental influences like stressful life experience. Studies have demonstrated thousands of genetic differences are associated with schizophrenia; however we do not understand the impact of these differences, or how stress experience may influence these differences in DNA. In this project we use molecular biology techniques to examine identified differences in the DNA of people suffering from schizophrenia in stress models. This research will help us to identify mechanisms that lead to schizophrenia vulnerability.

Need/Problem: Schizophrenia is a heritable disorder, but it is influenced by environmental factors. One of these factors is stressful life experience. Due to ethical considerations, it is impossible to test how stress experience influences the expression of genes in neurons of persons suffering from schizophrenia. 

Grant Summary: Dysregulation of the hormonal stress response is observed across the spectrum of schizophrenia from the first psychotic episode to chronic schizophrenia. As stress hormones can directly regulate DNA transcription processes, we aim to understand how stress experience engages the particular genetic variation associated with schizophrenia. 

Goals and Projected Outcomes: This study will identify schizophrenia associated single nucleotide polymorphisms (SNPs) that are engaged by various stress experience, allowing for more detailed study of which genes are directly regulated by this genetic variation in patients with schizophrenia. This exploratory work will be the launching point of several follow up studies to mechanistically examine this genetic variation. In addition, this formally establishes the collaboration between the Won and McElligott labs which will allow for the future submission of multi-PI grants to the NIH. 

Zoe McElligott, PhD

Hyejung Won, PhD

Grant Details: Using massively parallel reporter assays in combination with adeno-associated virus we will deliver DNA fragments containing genome wide association study (GWAS) verified SNPs to the prefrontal cortex of mice. Following recovery, we will present behavioral (acute and chronic stress) and pharmacological challenges (corticosterone in the drinking water) to the mice designed to alter their physiological stress response, and then quantitatively probe for the expression of the bar-coded virus using RNA sequencing (RNAseq). This will allow us to simultaneously investigate the regulation of over 5,000 individual SNPs by stress experience.