Data from: Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed Lewy Body disease

Objective: Variants in GBA are associated with Lewy Body (LB) pathology.
We investigated whether variants in other lysosomal storage disorder (LSD)
genes also contribute to disease pathogenesis. Methods: We performed a
genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1
in 231 brain autopsies. Brain autopsies included neuropathologically
defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without
significant LB pathology (n = 71), Alzheimer disease and lewy body variant
(ADLBV) (n = 68), and control brains without LB or AD neuropathology (n =
33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by ‘gene wise’
genetic association analysis was performed. To determine the functional
effect, a biochemical analysis of GBA in a subset of brains was also
performed. GCase activity was measured in a subset of brain samples (n =
64) that included LBD brains, with or without GBA mutations, and control
brains. A lipidomic analysis was also performed in brain autopsies (n =
67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and
control brains (n = 17), comparing GBA mutation carriers to non-carriers.
Results: In a ‘gene-wise’ analysis, variants in GBA, SMPD1 and MCOLN1 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 GBA
mutation carriers compared to non-carriers (p<0.001). A significant
increase and accumulation of several species for the lipid classes,
ceramides and sphingolipids, was observed in LBD brains carrying GBA
mutations compared to controls (p range: p<0.05-p<0.01).
Interpretation: Our study indicates that variants in GBA, SMPD1 and MCOLN1
are associated with LB pathology. Biochemical data comparing GBA mutation
carrier to non-carriers support these findings, which have important
implications for biomarker development and therapeutic strategies.