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

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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. Interpretation: 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.

Original languageEnglish (US)
Pages (from-to)810-820
Number of pages11
JournalAnnals of Clinical and Translational Neurology
Volume2
Issue number8
DOIs
StatePublished - Aug 1 2015

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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    Tosto, G., Fu, H., Vardarajan, B. N., Lee, J. H., Cheng, R., Reyes-Dumeyer, D., Lantigua, R., Medrano, M., Jimenez-Velazquez, I. Z., Elkind, M. S. V., Wright, C. B., Sacco, R. L., Pericak-Vance, M., Farrer, L., Rogaeva, E., St George-Hyslop, P., Reitz, C., & Mayeux, R. (2015). F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease. Annals of Clinical and Translational Neurology, 2(8), 810-820. https://doi.org/10.1002/acn3.223