Role of GBA variants in Lewy body disease neuropathology

AbstractRare and commonGBA variants are risk factors for both Parkinson ’s disease (PD) and dementia with Lewy bodies (DLB). However, the degree to whichGBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rareGBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing ofGBA exons revealed a total of 42 different variants (4 common [MAF  >  0.5%], 38 rare [MAF <  0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10,P <  0.001). In gene-burden analysis, presence of the minor allele for anyGBA variant was associated with increased odds of a high likelihood of DLB (OR  = 2.00,P <  0.001), a lower Braak NFT stage (OR = 0.48,P <  0.001), a lower Thal amyloid phase (OR = 0.55,P <  0.001), and a lower pS65-Ub level (β: −0.37,P <  0...
Source: Acta Neuropathologica - Category: Neurology Source Type: research