Establishing the Cohort for Occupational Risk and Prevention Studies for Amyotrophic Lateral Sclerosis (ALS CORPS)

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ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive, fatal motor neuron disease that likely results from a combination of lifetime non-genetic exposures—defined as the ALS exposome—and underlying genetic risk. Through ALS case-control studies, we identified that workers in Production Occupations and with occupational metal exposures carry a higher ALS risk; thus, we are interested in understanding how these occupational exposures and the exposome interact with genetics to inform ALS prevention efforts. In response to RFA-TS- 23-001 Funding Option A, we will address this need by establishing a longitudinal cohort of individuals at higher ALS risk, enriched by occupation and occupational metal exposure, to facilitate ALS gene and exposome studies. In this prospective longitudinal cohort of at-risk individuals, we will monitor the ALS exposome, polygenic risk, and phenoconversion in real time. Our overall objective is to identify cumulative risk factors that contribute to ALS phenoconversion. Our central hypothesis is that the ALS exposome and underlying genetic risk contribute to disease phenoconversion and provide targets for ALS prevention. We are guided by preliminary data showing that: i) work in Production Occupations and occupational metal exposure strongly associate with ALS risk, ii) factors beyond occupational exposures also contribute to ALS risk, and iii) genetic architecture by polygenic risk contributes to ALS risk. Our rationale is that a prospective cohort will enable ascertainment of critical exposure windows or exposure interactions, which can be targeted to prevent ALS phenoconversion in persons at higher risk. We will test the central hypothesis via three aims. In Aim 1, we will establish a prospective, longitudinal cohort of 5,000 individuals with higher ALS risk based on established occupational risk factors by recruiting via targeted online postings. In Aim 2, we will use our detailed exposure assessment tools to ascertain occupational, residential, avocational, and lifestyle exposures (ALS exposome) which cumulatively contribute to ALS risk. We will also obtain early indicators of phenoconversion for all participants, including body mass index and mild motor and cognitive impairment, to establish the cohort’s exposure risks and phenoconversion indices at baseline, thereby allowing for future critical research on ALS risk and prevention. Finally, in Aim 3, we will determine the polygenic risk of ALS in the cohort by genotyping buccal DNA from participants to establish the baseline genetic risk to integrate with the ALS exposome. The proposed research is highly significant because we expect to (1) establish a first in kind, non-familial but at-risk ALS cohort with detailed baseline exposome phenotyping and assessment of phenoconversion markers and (2) assess polygenic risk to further stratify ALS risk. Longitudinal follow-up will identify the critical time windows when interventions can modify disease onset. This is a high impact proposal, expanding ALS research beyond a “treatment” only approach, to a paradigm that addresses a “prevention” approach.