F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease.
OBJECTIVE
In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.


METHODS
About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.


RESULTS
A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case-control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.


CONCLUSIONS
FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York.
Giuseppe
G
Tosto
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York.
Hongjun
H
Fu
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York.
Badri N
BN
Vardarajan
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York.
Joseph H
JH
Lee
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York.
Rong
R
Cheng
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York.
Dolly
D
Reyes-Dumeyer
Department of Medicine College of Physicians and Surgeons, School of Public Health, Columbia University New York, New York.
Rafael
R
Lantigua
School of Medicine, Pontificia Universidad Catolica Madre y Maestra Santiago, Dominican Republic.
Martin
M
Medrano
Department of Medicine, Geriatrics Program, School of Medicine, University of Puerto Rico San Juan, Puerto Rico.
Ivonne Z
IZ
Jimenez-Velazquez
The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York ; Department of Neurology, Columbia University New York, New York.
Mitchell S V
MS
Elkind
Evelyn F. McKnight Brain Institute and Departments of Neurology, Public Health Sciences, John T. McDonald Department of Human Genetics, University of Miami Miami, Florida, 33136.
Clinton B
CB
Wright
Evelyn F. McKnight Brain Institute and Departments of Neurology, Public Health Sciences, John T. McDonald Department of Human Genetics, University of Miami Miami, Florida, 33136 ; Neuroscience Program, Leonard M. Miller School of Medicine, University of Miami Miami, Florida, 33136.
Ralph L
RL
Sacco
Neuroscience Program, Leonard M. Miller School of Medicine, University of Miami Miami, Florida, 33136 ; The John P. Hussman Institute for Human Genomics, University of Miami Miami, Florida, 33136.
Margaret
M
Pericak-Vance
Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Biostatistics and Epidemiology, Boston University Schools of Medicine and Public Health Boston, Massachusetts.
Lindsay
L
Farrer
Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8.
Ekaterina
E
Rogaeva
Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8 ; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge Cambridge, CB2 0XY, United Kingdom.
Peter
P
St George-Hyslop
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York ; Department of Neurology, Columbia University New York, New York.
Christiane
C
Reitz
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York ; Department of Neurology, Columbia University New York, New York ; Department of Psychiatry, School of Public Health, Columbia University New York, New York ; Department of Epidemiology, School of Public Health, Columbia University New York, New York.
Richard
R
Mayeux