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

Department of Biology, Brigham Young University, Provo, UT, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2010; 21(3):833-42. DOI: 10.3233/JAD-2010-091711
Source: PubMed


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.

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    • "In amyloid-protein precursor (APP) transgenic mice, ApoE was shown to have an effect on the amount and structure of brain intraparenchymal deposits of A as well as cerebral amyloid angiopathy in an isoform-specific manner (4 > 3 > 2) [10] [11]. The APOE 4 allele has been recently confirmed to be associated with A phenotypes , including A deposition and cerebrospinal fluid (CSF) A 1-42 levels, but not with CSF tau levels [12]. Since approximately 50–60% of patients with AD carry an APOE 4 allele, additional genetic factors are assumed to contribute to the risk of AD. "
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    • "nfluence of specific SORL1 alleles on CSF biomarkers in AD patients had conflicting results . Three studies revealed an influence of SORL1 SNP alleles on abeta in CSF ( Alexopoulos et al . , 2011 ; Guo et al . , 2012 ; Kolsch et al . , 2008 ) , whereas another study did not find any relationship between SORL1 SNP variants and abeta levels in CSF ( Kauwe et al . , 2010 ) . A study with ADNI AD patients reported a significant association between rs668387 , rs3824968 , rs1010159 , and lower abeta level in CSF ( Alexopoulos et al . , 2011 ) . Our separate analyses of the ADNI data set led to similar results , with an association between the rs3824968 - A allele and rs1010159 - G allele and lower levels o"
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