Gene-wise association of variants in four XXXX genes in neuropathologically confirmed lewy body disease.

@entity2315 @entity54356 @entity21244 @entity12744 @entity15675 @entity1726 @entity13740 @entity195 @entity49630 @entity9932
OBJECTIVE: Variants in @entity15675 are associated with Lewy Body (LB) pathology. We investigated whether variants in other @entity2315 ( @entity2315 ) genes also contribute to disease pathogenesis. METHODS: We performed a genetic analysis of four @entity2315 genes including @entity15675 , @entity12744 , @entity54356 , and @entity49630 in 231 brain autopsies. Brain autopsies included neuropathologically defined @entity21244 without @entity195 ( @entity195 ) changes (n = 59), @entity195 without significant LB pathology (n = 71), @entity195 and lewy body variant (ADLBV) (n = 68), and control brains without LB or @entity195 neuropathology (n = 33). Sequencing of @entity12744 , @entity54356 , @entity49630 and @entity15675 followed by 'gene wise' genetic association analysis was performed. To determine the functional effect, a biochemical analysis of @entity15675 in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included @entity21244 brains, with or without @entity15675 mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included @entity21244 (n = 34), ADLBV (n = 3), @entity195 (n = 4), @entity1726 (n = 9) and control brains (n = 17), comparing @entity15675 mutation carriers to non-carriers. RESULTS: In a 'gene-wise' analysis, variants in @entity15675 , @entity54356 and @entity49630 were significantly associated with LB pathology (p range: 0.03-4.14 x10-5). Overall, the mean levels of GCase activity were significantly lower in @entity15675 mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, @entity9932 and @entity13740 , was observed in @entity21244 brains carrying @entity15675 mutations compared to controls (p range: p<0.05-p<0.01). INTERPRETATION: Our study indicates that variants in @entity15675 , @entity54356 and @entity49630 are associated with LB pathology. Biochemical data comparing @entity15675 mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies.
