title: Validating predicted biological effects of Alzheimer's disease associated SNPs using CSF biomarker levels.
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.
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.forename: Kevin
authors.initials: K
authors.lastname: Mayo
authors.forename: Wayne
authors.initials: W
authors.lastname: Latu
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Hinrichs
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000704:Analysis of Variance; D015415:Biomarkers / Q000134:cerebrospinal fluid; D015220:Calcium Channels / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D015415:Biomarkers; C530077:CALHM1 protein, human; D015220:Calcium Channels; C490895:GAB2 protein, human; D026502:LDL-Receptor Related Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human; D016875:tau Proteins