Gene-Environment-Time Interactions in Neurodegenerative Diseases: Hypotheses and Research Approaches.

Authors:
Walter G Bradley
Walter G Bradley
University of Miami School of Medicine
United States
Angeline S Andrew
Angeline S Andrew
Dartmouth Medical School
Hanover | United States
Bryan J Traynor
Bryan J Traynor
Laboratory of Neurogenetics
United States
Tanya H Butt
Tanya H Butt
Division of Molecular Imaging and Neuropathology and New York State Psychiatric Institute
Elijah W Stommel
Elijah W Stommel
University of Hawaii
United States

Ann Neurosci 2018 Dec 4;25(4):261-267. Epub 2018 Dec 4.

Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.

Background: Amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's diseases are age-related neurodegenerative diseases. ALS is not a single entity but a syndrome with many different causes. In all 3 diseases, gene mutations account for only 10-15% of cases. Many environmental and lifestyle factors have been implicated as risk factors for ALS, though none have been proven to cause the disease. It is generally believed that ALS results from interactions between environmental risk factors and genetic predisposing factors. The advent of next-generation sequencing and recent advances in research into environmental risk factors offer the opportunity to investigate these interactions.

Summary: We propose a hypothesis to explain the syndrome of ALS based on the interaction of many individual environmental risk factors with many individual genetic predisposing factors. We hypothesize that there are many such combinations of individual, specific, genetic, and environmental factors, and that each combination can lead to the development of the syndrome of ALS. We also propose a hypothesis that explains the overlap between the age-related neurodegenerations and their genetic underpinnings. Age and duration of exposure are crucial factors in these age-related neurodegenerative diseases, and we consider how these may relate to gene-environment interactions.

Key Messages: To date, genetic studies and environmental studies have investigated the causes of ALS separately. We argue that this univariate approach will not lead to discoveries of important gene-environment interactions. We propose new research approaches to investigating gene-environment interactions based on these hypotheses.

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Source
https://www.karger.com/Article/FullText/495321
Publisher Site
http://dx.doi.org/10.1159/000495321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470336PMC
December 2018
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