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Defining Biological Impacts of Common GWAS Variants for Schizophrenia

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Abstract

Schizophrenia and related psychotic disorders are highly polygenic. The vast majority of their associated risk variants lie in non-coding areas of the genome, making their biological impacts cryptic in nature. I describe in this dissertation the development and application of different genomic techniques for assigning biological relevance to known schizophrenia risk variants.

These risk variants are widely acknowledged to be enriched in regulatory elements in the genome, particularly in enhancers and silencers, which regulate gene expression in a cell type and temporally specific manner. In Chapter 1, I described a methodology I have helped drive in our lab to test for activity of hypothesized enhancers using AAV-based enhancer-reporter assays in vivo in postnatal mouse brain. In Chapter 2, I conducted this assay in juvenile and adolescent mice to test for regulatory activity at a prioritized set of noncoding schizophrenia risk SNPs. My results identified 39 active regulatory elements, 19 of which showed allelic differences in activity at the schizophrenia risk SNP. In Chapter 3, I collapsed both coding and noncoding common schizophrenia risk variants into their presumed targeted genes. I used gene ontology to divide these genes into a priori-selected hypothesized risk pathways. I subsequently tested for associations between these risk pathways and endophenotypes of psychotic disorders. Major findings showed associations between overall genome-wide risk and overall diagnosis of a psychotic disorder, as well as associations between glutamatergic and GABAergic polygenic risk and endophenotypes related to cognitive control and social functioning.

In my PhD, I used diverse methodologies to better characterize the mechanisms linking genomic schizophrenia risk variants to psychotic disorder symptoms. My findings highlighted the value of in vivo functional genomics screens, particularly for schizophrenia and other adolescent- and adult-onset disorders which are difficult to model using in vitro methods, and of using multiple levels of analysis to better define aberrant biology in psychiatric disorders.

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This item is under embargo until October 14, 2026.