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).


CONCLUSIONS
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.
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America; Center for Human Genetics, Columbia University, New York, New York, United States of America.
Lorraine N
LN
Clark
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
Robin
R
Chan
Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America.
Rong
R
Cheng
Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
Xinmin
X
Liu
Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America.
Naeun
N
Park
Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
Nancy
N
Parmalee
Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
Sergey
S
Kisselev
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
Etty
E
Cortes
Department of Neurology, New York University School of Medicine, New York, New York, United States of America; Department of Pediatrics, New York University School of Medicine, New York, New York, United States of America.
Paola A
PA
Torres
Department of Neurology, New York University School of Medicine, New York, New York, United States of America; Department of Pediatrics, New York University School of Medicine, New York, New York, United States of America.
Gregory M
GM
Pastores
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
Jean P
JP
Vonsattel
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America; Department of Neurology, Columbia University, New York, New York, United States of America.
Roy
R
Alcalay
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America; Department of Neurology, Columbia University, New York, New York, United States of America.
Karen
K
Marder
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America; Department of Neurology, Columbia University, New York, New York, United States of America.
Lawrence L
LL
Honig
Department of Neurology, Columbia University, New York, New York, United States of America.
Stanley
S
Fahn
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America; Department of Neurology, New York University School of Medicine, New York, New York, United States of America; Department of Neurology, Columbia University, New York, New York, United States of America; Department of Psychiatry, and Department of Statistics, Columbia University, New York, New York, United States of America; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America; Center for Human Genetics, Columbia University, New York, New York, United States of America.
Richard
R
Mayeux
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
Michael
M
Shelanski
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
Gilbert
G
Di Paolo
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America; Center for Human Genetics, Columbia University, New York, New York, United States of America.
Joseph H
JH
Lee
D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D001921:Brain / Q000473:pathology; D003710:Demography; D005006:Ethnicity / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005962:Glucosylceramidase / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D020961:Lewy Body Disease / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D008055:Lipids / Q000097:blood; D016464:Lysosomal Storage Diseases / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000473:pathology*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
D008055:Lipids; D005962:Glucosylceramidase