Replication of BIN1 Association with Alzheimer's Disease and Evaluation of Genetic Interactions

Article type: Research Article

Authors: Carrasquillo, Minerva M.^{a; 1} | Belbin, Olivia^{a; b; 1} | Hunter, Talisha A.^a | Ma, Li^a | Bisceglio, Gina D.^a | Zou, Fanggeng^a | Crook, Julia E.^c | Pankratz, V. Shane^d | Sando, Sigrid B.^{e; f} | Aasly, Jan O.^{e; f} | Barcikowska, Maria^g | Wszolek, Zbigniew K.^h | Dickson, Dennis W.^a | Graff-Radford, Neill R.^{a; h} | Petersen, Ronald C.^{i; j} | Morgan, Kevin^b | for the Alzheimer's Research Trust Consortium (ART)^† | Younkin, Steven G.^{a; *}

Affiliations: [a] Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA | [b] School of Molecular Medical Sciences, Institute of Genetics, Queens's Medical Centre, University of Nottingham, Nottingham, UK | [c] Biostatistics Unit, Mayo Clinic College of Medicine, Jacksonville, FL, USA | [d] Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA | [e] Department of Neurology, St. Olav's Hospital, Trondheim, Norway | [f] Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway | [g] Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland | [h] Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, USA | [i] Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA | [j] Mayo Alzheimer Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA

Correspondence: [*] Correspondence to: Steven G. Younkin, MD, PhD, Department of Neuroscience, Mayo Clinic College of medicine, 4500 San Pablo Rd, Birdsall Building, Jacksonville, FL 32224, USA. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [†] The Alzheimer’s Disease Research Trust Consortium: Peter Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Queen’s University Belfast, UK; Reinhard Heun (now at Royal Derby Hospital), Heike Kölsch, University of Bonn, Germany; Patrick G. Kehoe, University of Bristol, UK; Nigel M. Hooper, Emma R.L.C. Vardy, University of Leeds, UK (now at University of Manchester); David M. Mann, University of Manchester, UK; Kristelle Brown, Noor Kalsheker, Kevin Morgan, University of Nottingham, UK; A. David Smith, Gordon Wilcock, Donald Warden, University of Oxford (OPTIMA), UK, Clive Holmes, University of Southampton, UK.

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.

Keywords: Alzheimer's disease, case-control studies, heterogeneity, late onset, meta-analysis

DOI: 10.3233/JAD-2011-101932

Journal: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 751-758, 2011