Open AccessF‐box/ LRR ‐repeat protein 7 is genetically associated with Alzheimer's disease
Author(s) -
Tosto Giuseppe,
Fu Hongjun,
Vardarajan Badri N.,
Lee Joseph H.,
Cheng Rong,
ReyesDumeyer Dolly,
Lantigua Rafael,
Medrano Martin,
JimenezVelazquez Ivonne Z.,
Elkind Mitchell S. V.,
Wright Clinton B.,
Sacco Ralph L.,
PericakVance Margaret,
Farrer Lindsay,
Rogaeva Ekaterina,
St GeorgeHyslop Peter,
Reitz Christiane,
Mayeux Richard
Publication year - 2015
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.223
Subject(s) - locus (genetics) , genetics , single nucleotide polymorphism , context (archaeology) , disease , gene , linkage disequilibrium , medicine , genome wide association study , genetic association , snp , biology , genotype , paleontology
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 rT g4510) 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 FBXL 7 (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 FBXL 7, 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.