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© 2010 American Academy of Neurology Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer diseaseFrom the Department of Neuroscience (F.Z., M.M.C., O.B., M.A., S.L.W., L.M., L.P.W., N.K., J.D.B., L.H.Y., Samuel G.Y., C.S.Y., G.D.B., D.W.D., Steven G.Y., N.E.-T.), Biostatistics Unit (J.E.C.), and Department of Neurology (N.G.-R., N.E.-T.), Mayo Clinic College of Medicine, Jacksonville, FL; Division of Biomedical Statistics and Informatics (V.S.P.), Mayo Clinic and Mayo Foundation, Rochester, MN; Department of Clinical Chemistry (K.M.), Institute of Genetics, Queens's Medical Centre, University of Nottingham, UK; and Department of Neurology and the Mayo Alzheimer Disease Research Center (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN. Address correspondence and reprint requests to Dr. N. Ertekin-Taner, Departments of Neurology and Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224 taner.nilufer{at}mayo.edu Background: Late-onset Alzheimer disease (LOAD) is a common disorder with a substantial genetic component. We postulate that many disease susceptibility variants act by altering gene expression levels. Methods: We measured messenger RNA (mRNA) expression levels of 12 LOAD candidate genes in the cerebella of 200 subjects with LOAD. Using the genotypes from our LOAD genome-wide association study for the cis-single nucleotide polymorphisms (SNPs) (n = 619) of these 12 LOAD candidate genes, we tested for associations with expression levels as endophenotypes. The strongest expression cis-SNP was tested for AD association in 7 independent case-control series (2,280 AD and 2,396 controls).
Results: We identified 3 SNPs that associated significantly with IDE (insulin degrading enzyme) expression levels. A single copy of the minor allele for each significant SNP was associated with Conclusions: These results provide strong evidence that IDE is a late-onset Alzheimer disease (LOAD) gene with variants that modify risk of LOAD by influencing IDE expression. They also suggest that the use of expression levels as endophenotypes in genome-wide association studies may provide a powerful approach for the identification of disease susceptibility alleles.
Abbreviations: AD = Alzheimer disease; CI = confidence interval; GWAS = genome-wide association study; LOAD = late-onset Alzheimer disease; mRNA = messenger RNA; OR = odds ratio; SNP = single nucleotide polymorphism.
Supplemental data at www.neurology.org *These authors contributed equally. Disclosure: Author disclosures are provided at the end of the article. Received July 22, 2009. Accepted in final form November 5, 2009.
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twofold higher IDE expression levels. The most significant SNP, rs7910977, is 4.2 kb beyond the 3' end of IDE. The association observed with this SNP was significant even at the genome-wide level (p = 2.7 x 10–8). Furthermore, the minor allele of rs7910977 associated significantly (p = 0.0046) with reduced LOAD risk (OR = 0.81 with a 95% CI of 0.70-0.94), as expected biologically from its association with elevated IDE expression. 