TY - JOUR
T1 - Gene-Environment-Time Interactions in Neurodegenerative Diseases
T2 - Hypotheses and Research Approaches
AU - Bradley, Walter G.
AU - Andrew, Angeline S.
AU - Traynor, Bryan J.
AU - Chiò, Adriano
AU - Butt, Tanya H.
AU - Stommel, Elijah W.
N1 - Funding Information:
Dr. Walter G. Bradley has received grants from NIH (NINDS), the Centers for Disease Control and Prevention (ATS-DR National ALS Registry), the ALS Association, the Muscular Dystrophy Association, and other foundations, and from nu- merous pharmaceutical companies for participation in therapeutic trials and data safety monitoring committees. He was formerly a consultant for Gerson Lehrman Group. He is the chairman of the Advisory Committee of the Institute of Ethnomedicine for which he receives an honorarium. Dr. Elijah W. Stommel has received grants from the Centers for Disease Control and Prevention (ATSDR National ALS Registry), the ALS Association, and other foundations, and from pharmaceutical companies for participation in therapeutic trials. Dr. Angeline S. Andrew has received grants from NIH, the Centers for Disease Control and Prevention (ATSDR National ALS Registry), and the ALS Association. Dr. Bryan J. Traynor has received research grants from the Myasthenia Gravis Foundation, the Robert Packard Center for ALS Research, the ALS Association, the Italian Football Federation (FIGC), the Center for Disease Control and Prevention, the Muscular Dystrophy Association, Merck Inc, and Microsoft Research. Dr. Traynor is part of the Intramural Research Program at the National Institutes of Health and receives funding through the Intramural Research Program. Dr. Traynor holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Dr. Adria-no Chiò has received grant from the European Union, the Italian Ministry of Health, and the Italian Ministry of Education, University and Research. He has received personal compensations for the participation to scientific boards by Mitsubishi Tanabe, Cytokinetics, Roche and Italfarmaco. T.H.B. has no conflicts of interest to declare.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis
KW - Environmental risk factors
KW - Gene-environment-time interactions
KW - Genetic predisposition
KW - Neurodegenerative diseases
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U2 - 10.1159/000495321
DO - 10.1159/000495321
M3 - Article
AN - SCOPUS:85058183781
VL - 25
SP - 261
EP - 267
JO - Annals of Neurosciences
JF - Annals of Neurosciences
SN - 0972-7531
IS - 4
ER -