Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions

Minerva M Carrasquillo, Talisha A. Hunter, Li Ma, Gina D. Bisceglio, Fanggeng Zou, Juliana Crook, V. Shane Pankratz, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff Radford, Ronald Carl Petersen, Kevin Morgan, Steven G Younkin

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48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)751-758
Number of pages8
JournalJournal of Alzheimer's Disease
Volume24
Issue number4
DOIs
StatePublished - 2011

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Keywords

  • Alzheimer's disease
  • case-control studies
  • heterogeneity
  • late onset
  • meta-analysis

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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