title: Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions.
abstract: The most recent late-onset Alzheimer's disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 × 10-11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 × 10-9). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR = 1.17, p = 1.1 × 10-4) comparable to that previously reported (OR = 1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p = 0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p = 3.8 × 10-20). We also tested for epistatic interaction between these variants and APOE ε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1: rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224 , USA.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.forename: Olivia
authors.initials: O
authors.lastname: Belbin
authors.forename: Talisha A
authors.initials: TA
authors.lastname: Hunter
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Gina D
authors.initials: GD
authors.lastname: Bisceglio
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.forename: Julia E
authors.initials: JE
authors.lastname: Crook
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Sigrid B
authors.initials: SB
authors.lastname: Sando
authors.forename: Jan O
authors.initials: JO
authors.lastname: Aasly
authors.forename: Maria
authors.initials: M
authors.lastname: Barcikowska
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D016015:Logistic Models; D009687:Nuclear Proteins / Q000235:genetics*; D016017:Odds Ratio; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins