A Study of the SORL1 Gene in Alzheimer's Disease and Cognitive Function

Article type: Research Article

Authors: Liu, Fan^{a; *} | Ikram, M. Arfan^b | Janssens, A. Cecile J.W.^b | Schuur, Maaike^{a; c} | de Koning, Inge^c | Isaacs, Aaron^a | Struchalin, Maksim^a | Uitterlinden, Andre G.^{b; d} | den Dunnen, Johan T.^e | Sleegers, Kristel^{f; g} | Bettens, Karolien^{f; g} | Van Broeckhoven, Christine^{f; g} | van Swieten, John^c | Hofman, Albert^b | Oostra, Ben A.^a | Aulchenko, Yurii S.^a | Breteler, Monique M. B.^b | van Duijn, Cornelia M.^{a; **}

Affiliations: [a] Genetic Epidemiology Unit, Erasmus Medical Center, Rotterdam, The Netherlands | [b] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands | [c] Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands | [d] Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands | [e] Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands | [f] Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium | [g] University of Antwerp, Antwerpen, Belgium

Correspondence: [**] Corresponding author: Prof. Cornelia M van Duijn, Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, Dr. Molewaterplein 50, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. Tel.: +31 10 7043394; Fax: +31 10 7089406; E-mail: c.vanduijn@erasmusmc.nl.

Note: [*] Present affiliation: Department of Forensic Molecular Biology, Erasmus Medical Center, Rotterdam, The Netherlands.

Note: [] Communicated by Maire Percy

Abstract: Several studies have investigated the role of the neuronal sortilin-related receptor (SORL1) gene in Alzheimer's disease (AD), but findings have been inconsistent. We conducted a study of 7 single nucleotide polymorphisms (SNPs), rs668387, rs689021, rs641120, rs1699102, rs3824968, rs2282649, and rs1010159, in the SORL1 gene that were associated to AD in previous studies. We tested for association with AD and cognitive function in 6741 participants of the Rotterdam Study and in 2883 individuals from the Erasmus Rucphen Family study. We performed meta-analyses on AD using our data together with those of previous studies published prior to September 2008 in Caucasians. Further, we studied up to 76 SNPs in a 400 kb region within and flanking the gene to evaluate the evidence that other genetic variants are associated with AD or cognitive function. There was no significant evidence for association between SORL1 SNPs and incident AD patients in the Rotterdam Study. In a meta-analysis of our data with those of others, six out of seven SNPs attained borderline significance. However, removal of the first study reporting association from the meta-analysis resulted in non-significant odds ratios for all SNPs. SNPs rs668387, rs689021, and rs641120 were associated with cognitive function in non-demented individuals at borderline statistical significance in two independent Dutch cohorts, but in the opposite direction. Testing for association using dense SNPs in the SORL1 gene did not reveal significant association with AD, or with cognitive function when adjusting for multiple testing. In conclusion, our data do not support the hypothesis that genetic variants in SORL1 are related to the risk of AD.

Keywords: Alzheimer's disease, association, cognitive function, SORL1

DOI: 10.3233/JAD-2009-1137

Journal: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 51-64, 2009