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.

研究目的：GBA基因变异与路易体（Lewy Body, LB）病理密切相关。本研究旨在探讨其他溶酶体贮积症（lysosomal storage disorder, LSD）相关基因的变异是否同样参与疾病的发病机制。
研究方法：我们对231例脑尸检样本中的4个LSD相关基因（包括GBA、HEXA、SMPD1及MCOLN1）开展了遗传分析。本次纳入的脑尸检样本按神经病理特征分为4组：无阿尔茨海默病（Alzheimer Disease, AD）病理改变的路易体痴呆（Lewy Body Dementia, LBD）组（n=59）、无明显路易体病理的AD组（n=71）、阿尔茨海默病伴路易体变异型（Alzheimer disease and lewy body variant, ADLBV）组（n=68），以及无路易体或AD神经病理改变的对照脑组织组（n=33）。首先对HEXA、SMPD1、MCOLN1及GBA进行测序，随后开展"gene-wise"遗传关联分析。为明确基因变异的功能效应，我们还对部分脑组织样本开展了GBA的生化分析：对64例包含伴/不伴GBA突变的LBD脑组织及对照脑组织的样本，检测了葡糖脑苷脂酶（Glucocerebrosidase, GCase）活性。此外，我们对67例脑尸检样本开展了脂质组学分析，涵盖LBD组（n=34）、AD组（n=4）、ADLBV组（n=3）、帕金森病（Parkinson Disease, PD）组（n=9）及对照组（n=17），并比较了GBA突变携带者与非携带者的脂质组学差异。
研究结果："gene-wise"分析显示，GBA、SMPD1及MCOLN1的基因变异与路易体病理显著相关（p值范围：0.03~4.14×10^-5）。总体而言，GBA突变携带者的GCase平均活性水平显著低于非携带者（p<0.001）。与对照组相比，携带GBA突变的LBD脑组织中，神经酰胺（ceramides）与鞘脂（sphingolipids）两类脂质的多种分子物种出现了显著升高与蓄积（p值范围：p<0.05~p<0.01）。
研究解读：本研究证实GBA、SMPD1及MCOLN1的基因变异与路易体病理相关。对比GBA突变携带者与非携带者的生化数据验证了上述结论，该发现对生物标志物开发与治疗策略研发具有重要指导意义。