Interactions of Gut Microbiome, Genetic Susceptibility, and Environmental Factors in Parkinson s Disease
Abstract
Parkinson s disease (PD) is a common, progressive, and debilitating disease that currently cannot be prevented or cured. The cause for most cases of PD is unknown and is suspected to involve complex interactions between genes and environmental factors. Genetic studies have identified dozens of genetic risk factors, but each has a small effect and together they account for only a fraction of the genetic component in PD (i.e., there must exist additional genes that have not been discovered yet). Epidemiological studies have identified several elements, most notably, association of exposure to herbicides/pesticides with increased risk, and of cigarette smoking and caffeinated coffee consumption with reduced risk of PD. However, as with genetic factors, individual effects of environmental risk factors on the odds of developing PD are small. None of the known risk factors, genetic or environmental, are sufficient to cause disease, not individually, not in combination, and not in interaction. There must be more to gene-environment interaction in PD than the 23 human chromosomes and the environmental factors we know of. This proposal is in response to a DoD request for application with the focus area "Studies to identify gene-environment interaction in Parkinson s disease cohorts." Gene-environment interaction has traditionally meant human genome (G) x exposure (E). We and others have conducted extensive research in this area, but we have been ignoring the microbiome, because, until recently, we did not appreciate its monumental effect on human health. Interestingly, in the GxE equation, the microbiome can be regarded as genes or as environment. This dual nature offers the best of both worlds: defined as the collective genomes of microorganisms living in our gut, the gut microbiome is measured and analyzed with the precision of molecular genetic techniques, but, unlike the nuclear genome, which is inherited and almost immutable, the composition of the microbiome can be easily modified to prevent and treat disease. This project is built on the strong infrastructure of the NeuroGenetics Research Consortium (NGRC), which includes one of the largest PD datasets in the world, and one the few that has collected both genomic and environmental data. Using this dataset, NGRC pioneered genomewide gene-environment interaction and identified genes that interact with the effects of smoking and caffeine on PD risk. Importantly, even the gene-environment interactions could not explain PD risk completely, leading us to believe that we are missing a critical piece. We and others have shown that the gut microbiome is altered in PD, but the specifics on the organisms that are involved have not been worked out. Recently, we discovered evidence that suggests a specific bacterial genus (a potential pathogen that we detected in the gut microbiome of individuals with PD) is the trigger that causes genetically susceptible individuals to develop PD. We also uncovered evidence for involvement of microbiome-driven pathways that degrade herbicides that increase PD risk. We propose a large, comprehensive, and powerful study on the interaction of genes, environment, and microbiome in PD. Introducing the microbiome will open a new field in PD research. We will identify the organisms and microbial pathways that contribute to risk and protection against PD. We will identify the microorganisms that interact with genetic risk factors of PD and whose presence or absence is the determining factor for who will progress to PD and who will not. We will identify the organisms that interact with environmental risk factors and enhance or abolish their effect on PD risk. We will identify the changes in the gut microbiome that precede PD vs. changes that are caused by PD progression and changes that are caused by PD medications. A massive dataset will be generated in this study, which we will share publicly with other researchers to use in their studies. Microbiome i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810509
Entities
People
- David G. Standaert
Organizations
- United States Army
- University of Alabama at Birmingham