Alzheimer's disease risk variants show association with cerebrospinal fluid amyloid beta.
The use of quantitative endophenotypes in genetic studies may provide greater power, allowing for the use of powerful statistical methods and a biological model for the effects of the disease-associated genetic variation. Cerebrospinal fluid (CSF) amyloid beta (Abeta) levels are promising endophenotypes for late-onset Alzheimer's disease (LOAD) and show correlation with LOAD status and Abeta deposition. In this study, we investigated 29 single nucleotide polymorphisms (SNPs) positive in AlzGene ( http://www.alzgene.org ) meta-analyses, for association with CSF Abeta levels in 313 individuals. This study design makes it possible to replicate reported LOAD risk alleles while contributing novel information about the mechanism by which they might affect that risk. Alleles in ACE, APOE, BDNF, DAPK1, and TF are significantly associated with CSF Abeta levels. In vitro analysis of the TF SNP showed a change in secreted Abeta consistent with the CSF phenotype and known Alzheimer's disease variants, demonstrating the utility of this approach in identifying SNPs that influence risk for disease via an Abeta-related mechanism.
Kauwe
John S K
JS
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Wang
Jun
J
Mayo
Kevin
K
Morris
John C
JC
Fagan
Anne M
AM
Holtzman
David M
DM
Goate
Alison M
AM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D030541:Databases, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012306:Risk
D016229:Amyloid beta-Peptides