We aim to quantify how genetic variation in axon-survival/destruction, inflammasome signaling, lipid and lysosomal function, and clinical exposures (e.g., chemotherapy), shape risk, onset, and progression of neurological, metabolic, and neuro-immune conditions. We will leverage UK Biobank (UKB) sequencing and linked health records to develop a hypothesis-driven portrait of the global genetics across the following disease axes, which we will use (and publish) to inform clinical trial design, biomarker strategies, and disease understanding:
*Axon integrity axis: Protein-altering/LoF variants in NMNAT2 and functional variation in SARM1 (executioner of programmed axon degeneration) modify risk or course of neurodegenerative, neuropathic (eg, CIPN, DPN), and neuro-ophthalmic disease.
*Neuro-immune axis: NLRP3 gain-of-function (GoF) increases systemic inflammation, influencing metabolic traits (e.g., BMI and obesity) and neuro-immune phenotypes (e.g., MS risk or progression).
* Lipid homeostasis: Well-studied ApoE2/3/4 variants modify the risk and course of neurodegeneration.
*Lysosomal function axis: TMEM175 and TRPML1 variants confer risk or protection from Parkinson’s Disease, influencing age of onset, disease course, and manifestation (e.g., cognition vs motor function).
*Exposure × genotype: Neurotoxic therapies interact with genetic vulnerability (e.g., SARM1/NMNAT2) to modify neuropathy incidence, time-to-onset, and persistence.
*Progression modeling: Clinical/demographic features (e.g., age, lifestyle, treatment) together with genetics predict disease course and inform feasibility of trials with progression as the primary endpoint.