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

Research output: Contribution to journalArticle

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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

Fingerprint

Alzheimer Disease
Genome-Wide Association Study
Meta-Analysis
Logistic Models
Genes
Alleles
Odds Ratio
Regression Analysis
Genome

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

Cite this

Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions. / Carrasquillo, Minerva M; Hunter, Talisha A.; Ma, Li; Bisceglio, Gina D.; Zou, Fanggeng; Crook, Juliana; Pankratz, V. Shane; Sando, Sigrid B.; Aasly, Jan O.; Barcikowska, Maria; Wszolek, Zbigniew K; Dickson, Dennis W; Graff Radford, Neill R; Petersen, Ronald Carl; Morgan, Kevin; Younkin, Steven G.

In: Journal of Alzheimer's Disease, Vol. 24, No. 4, 2011, p. 751-758.

Research output: Contribution to journalArticle

Carrasquillo, Minerva M ; Hunter, Talisha A. ; Ma, Li ; Bisceglio, Gina D. ; Zou, Fanggeng ; Crook, Juliana ; Pankratz, V. Shane ; Sando, Sigrid B. ; Aasly, Jan O. ; Barcikowska, Maria ; Wszolek, Zbigniew K ; Dickson, Dennis W ; Graff Radford, Neill R ; Petersen, Ronald Carl ; Morgan, Kevin ; Younkin, Steven G. / Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions. In: Journal of Alzheimer's Disease. 2011 ; Vol. 24, No. 4. pp. 751-758.
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AU - Carrasquillo, Minerva M

AU - Hunter, Talisha A.

AU - Ma, Li

AU - Bisceglio, Gina D.

AU - Zou, Fanggeng

AU - Crook, Juliana

AU - Pankratz, V. Shane

AU - Sando, Sigrid B.

AU - Aasly, Jan O.

AU - Barcikowska, Maria

AU - Wszolek, Zbigniew K

AU - Dickson, Dennis W

AU - Graff Radford, Neill R

AU - Petersen, Ronald Carl

AU - Morgan, Kevin

AU - Younkin, Steven G

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