Neuronopathic Gaucher disease is a rare and severe neurodegenerative lysosomal disorder caused by pathogenic variants in the GBA1 gene. Although GBA1 deficiency is necessary for disease, neurological involvement varies widely between individuals, and there are currently no effective treatments for central nervous system manifestations. This variability suggests that additional genetic factors modify neurological vulnerability downstream of GBA1 dysfunction.
The primary research question of this project is: which genetic modifiers influence neurological and neurodegenerative outcomes in individuals carrying pathogenic GBA1 variants, and can these modifiers highlight novel therapeutic targets for neuronopathic Gaucher disease?
The objectives of the study are to:
(1) identify UK Biobank participants carrying pathogenic or likely pathogenic GBA1 variants using whole-exome sequencing data;
(2) characterise neurological and neurodegenerative phenotypes associated with GBA1 variation using linked health records, mortality data, and cognitive measures; and
(3) identify and genetically validate modifier genes and biological pathways associated with increased or reduced neurological risk among GBA1 variant carriers.
The scientific rationale is that human genetic analyses provide a powerful and unbiased approach for discovering disease-modifying pathways, particularly in rare disorders where traditional clinical cohorts are small and highly selected. The UK Biobank uniquely enables this work by combining large-scale sequencing with longitudinal, population-based health outcomes. By anchoring target identification directly in human data, this project aims to prioritise biologically meaningful and potentially druggable pathways involved in Gaucher-related neurodegeneration. The findings will advance understanding of disease mechanisms and support the identification of novel, human-validated therapeutic targets for future translational research.