Validating predicted biological effects of Alzheimer's disease associated SNPs using CSF biomarker levels

John S.K. Kauwe, Carlos Cruchaga, Sarah Bertelsen, Kevin Mayo, Wayne Latu, Petra Nowotny, Anthony L. Hinrichs, Anne M. Fagan, David M. Holtzman, Disease Neuroimaging Initiative Alzheimer'S Disease Neuroimaging Initiative, Alison M. Goate

Research output: Contribution to journalArticle

38 Scopus citations

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.

Original languageEnglish
Pages (from-to)833-842
Number of pages10
JournalJournal of Alzheimer's Disease
Volume21
Issue number3
DOIs
StatePublished - 2010

Keywords

  • Alzheimer's disease
  • CALHM1
  • GAB2
  • SORL1
  • amyloid
  • association
  • endophenotypes
  • genetics
  • tau

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    Kauwe, J. S. K., Cruchaga, C., Bertelsen, S., Mayo, K., Latu, W., Nowotny, P., Hinrichs, A. L., Fagan, A. M., Holtzman, D. M., Alzheimer'S Disease Neuroimaging Initiative, D. N. I., & Goate, A. M. (2010). Validating predicted biological effects of Alzheimer's disease associated SNPs using CSF biomarker levels. Journal of Alzheimer's Disease, 21(3), 833-842. https://doi.org/10.3233/JAD-2010-091711