Validating Predicted Biological Effects of Alzheimer's Disease Associated SNPs Using CSF Biomarker Levels

Article type: Research Article

Authors: Kauwe, John S.K.^{a; 1} | Cruchaga, Carlos^{b; 1} | Bertelsen, Sarah^b | Mayo, Kevin^b | Latu, Wayne^a | Nowotny, Petra^b | Hinrichs, Anthony L.^b | Fagan, Anne M.^c | Holtzman, David M.^c | Alzheimer's Disease Neuroimaging Initiative, ² | Goate, Alison M.^{b; *}

Affiliations: [a] Department of Biology, Brigham Young University, Provo, UT, USA | [b] Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA | [c] Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

Correspondence: [*] Correspondence to: Alison M. Goate, PhD, Samuel and Mae S. Ludwig Professor, Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Tel.: +1 314 362 8691; Fax: +1 314 747 2983; E-mail: goatea@psychiatry.wustl.edu.

Note: [1] Co-first authors with equal contributions.

Note: [2] Some of the data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://www.loni.ucla.edu/ADNI). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. ADNI investigators include (complete listing available at http://www.loni.ucla.edu/ADNI/About/About_Investigators.shtml).

Note: [] Handling Associate Editor: Daniela Galimberti

Abstract: Recent large-scale genetic studies of late-onset Alzheimer's disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not definitively known. CALHM1 and SORL1 may alter amyloid-β (Aβ) levels and GAB2 may influence phosphorylation of the tau protein. In this study we have analyzed disease associated genetic variants in each of these genes for association with cerebrospinal fluid (CSF) Aβ or tau levels in 602 samples from two independent CSF series. We failed to detect association between CSF Aβ42 levels and single nucleotide polymorphisms in SORL1 despite substantial statistical power to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels, power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is marginally associated with CSF Aβ42 levels. This association is consistent with previous reports that this non-synonymous coding substitution results in increased Aβ levels in vitro and provides support for an Aβ-related mechanism for modulating risk for Alzheimer's disease.

Keywords: Alzheimer's disease, amyloid, association, CALHM1, endophenotypes, GAB2, genetics, SORL1, tau

DOI: 10.3233/JAD-2010-091711

Journal: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 833-842, 2010