Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies.
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.
Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Joshua T
JT
Geiger
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Jinhui
J
Ding
Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Barbara
B
Crain
Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Olga
O
Pletnikova
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Christopher
C
Letson
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Synder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Neuroregeneration Program, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ted M
TM
Dawson
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Liana S
LS
Rosenthal
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Alexander
A
Pantelyat
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
J Raphael
JR
Gibbs
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Marilyn S
MS
Albert
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Dena G
DG
Hernandez
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Argye E
AE
Hillis
Genetics and Pharmacogenomics, Merck Research Laboratories, West Point, PA, USA.
David J
DJ
Stone
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Andrew B
AB
Singleton
Department of Molecular Neuroscience, University College London, London, UK.
John A
JA
Hardy
Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Juan C
JC
Troncoso
Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: sonja.scholz@nih.gov.
Sonja W
SW
Scholz
D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003704:Dementia / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics; D020961:Lewy Body Disease / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009656:North America
APOE; APP; Alzheimer dementia; Dementia with Lewy bodies; Exome sequencing; GBA; Lewy body dementia; PSEN1