F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease

Giuseppe Tosto; Hongjun Fu; Badri N Vardarajan; Joseph H Lee; Rong Cheng; Dolly Reyes-Dumeyer; Rafael Lantigua; Martin Medrano; Ivonne Z Jimenez-Velazquez; Mitchell S V Elkind; Clinton B Wright; Ralph L Sacco; Margaret Pericak-Vance; Lindsay Farrer; Ekaterina Rogaeva; Peter St George-Hyslop; Christiane Reitz; Richard Mayeux

doi:10.1002/acn3.223

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F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease

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F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease

Giuseppe Tosto, Hongjun Fu, Badri N Vardarajan, Joseph H Lee, Rong Cheng, Dolly Reyes-Dumeyer, Rafael Lantigua, Martin Medrano, Ivonne Z Jimenez-Velazquez, Mitchell S V Elkind, …

Annals of clinical and translational neurology, Vol.2(8), pp.810-820

2015-08

DOI: https://doi.org/10.1002/acn3.223

PMCID: PMC4554442

PMID: 26339675

Abstract

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. 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. 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. 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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.57 Alzheimer's Disease
Web Of Science research areas: Clinical Neurology; Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease
Creators: Giuseppe Tosto - 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
Hongjun Fu - The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York
Badri N 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 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 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 Reyes-Dumeyer - 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
Rafael Lantigua - Department of Medicine College of Physicians and Surgeons, School of Public Health, Columbia University New York, New York
Martin Medrano - School of Medicine, Pontificia Universidad Catolica Madre y Maestra Santiago, Dominican Republic
Ivonne Z Jimenez-Velazquez - Department of Medicine, Geriatrics Program, School of Medicine, University of Puerto Rico San Juan, Puerto Rico
Mitchell S V Elkind - The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York ; Department of Neurology, Columbia University New York, New York
Clinton B 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
Ralph L Sacco - 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
Margaret Pericak-Vance - 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
Lindsay Farrer - Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Biostatistics and Epidemiology, Boston University Schools of Medicine and Public Health Boston, Massachusetts
Ekaterina 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
Peter St George-Hyslop - 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
Christiane 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
Richard Mayeux - 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
Publication Details: Annals of clinical and translational neurology, Vol.2(8), pp.810-820
Publisher: United States
Grant note: U24 AG056270 / NIA NIH HHS R01 AG037212 / NIA NIH HHS R01 AG041797 / NIA NIH HHS MC_G1000734 / Medical Research Council 089703 / Wellcome Trust RF1 AG015473 / NIA NIH HHS P50 AG008702 / NIA NIH HHS R37 NS029993 / NINDS NIH HHS R37 AG015473 / NIA NIH HHS 081864 / Wellcome Trust R01 NS029993 / NINDS NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Department of Neurology; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 26339675
PMCID: PMC4554442
Record Identifier: 991031577349902976