Identification of ALS risk factors leading to CHIP-related Epi-age acceleration

Most people with ALS have no family history of the disease or and no ALS-linked genetic mutations. Growing evidence suggests that ALS risk factors, such as military service, contact sports, traumatic brain injury, neuroinflammation, and exposure to infectious agents and/or industrial/environmental neurotoxins, may cause changes that affect the way genes work, leaving a unique epigenetic footprint that could be used as a marker for disease. One measure potentially associated with these changes is 'biological age.' Research assessing biological age (as opposed to the commonly used chronological age) in the blood and brains of people with ALS demonstrates that individuals who are biologically older develop ALS earlier and have a shorter length of disease. However, whether such age acceleration is linked to ALS risk factors is unclear. What is known is that age acceleration is associated with a genetic condition called clonal hematopoiesis of indeterminate potential (CHIP), which involves mutations in sections of DNA responsible for proper gene regulation. We hypothesize that exposure to certain risk factors leads to CHIP mutations, which in turn correspond to older biological age in people with ALS. To test our hypothesis, we will gather nearly 11,000 samples from datasets we have already generated, publicly available information and established collaborations. We will then calculate age acceleration in all samples, look for mutations in 220 CHIP-associated DNA regions and combine demographic/clinical information with CHIP-related age acceleration. We hope to uncover an ALS-specific footprint, which could be developed as a biomarker in the future.