All ETDs from UAB

Advisory Committee Chair

Haydeh Payami

Advisory Committee Members

David G Standaert

Elliot J Lefkowitz

Erik D Roberson

Hemant K Tiwari

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

GENE–ENVIRONMENT INTERACTION IN PARKINSON DISEASE: THE GUT MICROBIOME ZACHARY D. WALLEN GENETICS, GENOMICS, AND BIOINFORMATICS ABSTRACTParkinson disease (PD) is a progressive neurodegenerative disease with no cure. Majority of cases are idiopathic, and the cause is unknown. Studies have been conducted in human and animals to identify PD risk factors, resulting in a list of genetic and environmental factors that modestly increases risk of PD. Still, no individual risk factor fully explains the cause of PD, and neither has the combination of these factors. Additional avenues of research are being investigated to find potential triggers of PD, and factors that might modify the progression of PD. This includes research into the gut microbiome, as gut health perturbations are frequently documented and studies have shown a dysbiotic gut microbial community in PD. This also includes the search for genetic modifiers of PD onset, which might provide a mechanism to modify disease progression and prolong onset of PD. This dissertation focuses on both of the aforementioned areas of PD research. We first sought to identify genetic modifiers for idiopathic PD by performing a genome-wide association study (GWAS) of age at PD diagnosis using 2,000 PD patients. Then, we performed a microbiome-wide association study (MWAS) in two additional cohorts to characterize gut microbial alterations observed in PD. We then investigated if opportunistic pathogens found enriched in PD gut might interact with genetic susceptibility of PD.   From our GWAS of age at PD diagnosis, we detected two potentially independent signals associated with an earlier PD diagnosis of ~6 years in a gene involved in neuronal plasticity and response to injury. Our MWAS of the PD gut microbiome revealed 15 bacterial genera significantly associated with PD, three of which were opportunistic pathogens, enriched in PD, that were part of a poly-microbial group of correlated genera, also enriched in PD. We detected potential interaction between these opportunistic pathogens and genetic susceptibility of PD conferred by genetic variants at the 3′ end of SNCA, the gene most highly associated with PD risk, which codes for the pathological hallmark of PD. Results provide potential leads for further research in humans and animals to see if findings have biological implications for PD disease progression.

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