Integrating the exposome and epigenome identifies determinants of ALS risk, survival, and pathogenesis

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or meaningful treat- ments. ALS is mostly sporadic, and for most, evidence supports a gene-time-environment hypothesis of ALS triggered by a confluence of nonmodifiable risk factors (age, sex, and genetics) and modifiable risk factors from the exposome (a person’s cumulative lifetime exposures). Exposures imprint on the epigenome via DNA meth- ylation (DNAm) marks, which change with age, modifying cellular response to environmental insults. Compre- hensive knowledge of all these factors is needed to develop personalized prevention strategies for those at highest risk and personalized therapeutics for those already living with ALS. We reported that biofluid- and sur- vey-based exposure measures, summarized by environmental risk scores (ERS), strongly impact ALS risk and progression, adjusted for genetic background. We also recently discovered that epigenetic age acceleration, calculated from DNAm, is associated with ALS risk and exposures. However, the full spectrum of nonmodifia- ble and modifiable risk factors resulting changes in the epigenome are incompletely characterized. There is a critical need to fill this gap and determine how these factors impact ALS risk and the epigenome, leading to a better understanding of disease etiology, which can inform future precision strategies to prevent ALS. Our long-term goal is to leverage knowledge of the ALS exposome to inform personalized ALS prevention and therapeutic strategies. Our current objectives are to (i) comprehensively assess the exposome in our Michigan cohort and determine how it associates with ALS risk and survival; and (ii) gain insight into disease etiology by examining the intersection of the exposome with the ALS epigenome and transcriptome. Our central hypothe- sis is that ALS cases will have higher ERS scores, which correlate with epigenetic and transcriptomic changes and ALS risk and survival. In Aim 1, we will leverage targeted and untargeted exposomics in biofluids to identi- fy toxicant exposures that associate with ALS risk and survival and determine the effects of age, sex, and pol- ygenic risk on these outcomes. In Aim 2, we will identify geospatial- and survey-based exposomic measures linked to ALS risk and survival, and evaluate how they associate age, sex, polygenic risk, and biofluid toxicant measures. Finally, in Aim 3, we will characterize exposome-related DNAm and transcriptomic signatures and their association to ALS risk and survival. Completion of these studies will identify ALS-relevant exposome fac- tors that associate with to disease risk and survival via DNAm and consequent transcriptomic changes. These results will have important translational impact by lending insight into ALS etiology and identifying exposomic factors that most impact ALS risk and survival, thereby making the first critical steps towards personalized risk prediction and prevention strategies in ALS by exposure mitigation.