Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease

F. Zou, Minerva M Carrasquillo, V. S. Pankratz, O. Belbin, K. Morgan, M. Allen, S. L. Wilcox, L. Ma, L. P. Walker, N. Kouri, J. D. Burgess, L. H. Younkin, Samuel G. Younkin, C. S. Younkin, G. D. Bisceglio, Juliana Crook, Dennis W Dickson, Ronald Carl Petersen, Neill R Graff Radford, Steven G YounkinNilufer Taner

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Abstract

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 ∼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 × 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. 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.

Original languageEnglish (US)
Pages (from-to)480-486
Number of pages7
JournalNeurology
Volume74
Issue number6
DOIs
StatePublished - Feb 2010

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Endophenotypes
Genome-Wide Association Study
Insulysin
Alzheimer Disease
Single Nucleotide Polymorphism
Gene Expression
Alleles
Disease Susceptibility
Genes
Cerebellum
Genotype
Genome
Messenger RNA

ASJC Scopus subject areas

  • Clinical Neurology

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Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease. / Zou, F.; Carrasquillo, Minerva M; Pankratz, V. S.; Belbin, O.; Morgan, K.; Allen, M.; Wilcox, S. L.; Ma, L.; Walker, L. P.; Kouri, N.; Burgess, J. D.; Younkin, L. H.; Younkin, Samuel G.; Younkin, C. S.; Bisceglio, G. D.; Crook, Juliana; Dickson, Dennis W; Petersen, Ronald Carl; Graff Radford, Neill R; Younkin, Steven G; Taner, Nilufer.

In: Neurology, Vol. 74, No. 6, 02.2010, p. 480-486.

Research output: Contribution to journalArticle

Zou, F, Carrasquillo, MM, Pankratz, VS, Belbin, O, Morgan, K, Allen, M, Wilcox, SL, Ma, L, Walker, LP, Kouri, N, Burgess, JD, Younkin, LH, Younkin, SG, Younkin, CS, Bisceglio, GD, Crook, J, Dickson, DW, Petersen, RC, Graff Radford, NR, Younkin, SG & Taner, N 2010, 'Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease', Neurology, vol. 74, no. 6, pp. 480-486. https://doi.org/10.1212/WNL.0b013e3181d07654
Zou, F. ; Carrasquillo, Minerva M ; Pankratz, V. S. ; Belbin, O. ; Morgan, K. ; Allen, M. ; Wilcox, S. L. ; Ma, L. ; Walker, L. P. ; Kouri, N. ; Burgess, J. D. ; Younkin, L. H. ; Younkin, Samuel G. ; Younkin, C. S. ; Bisceglio, G. D. ; Crook, Juliana ; Dickson, Dennis W ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Younkin, Steven G ; Taner, Nilufer. / Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease. In: Neurology. 2010 ; Vol. 74, No. 6. pp. 480-486.
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abstract = "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 ∼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 × 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. 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.",
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T1 - Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease

AU - Zou, F.

AU - Carrasquillo, Minerva M

AU - Pankratz, V. S.

AU - Belbin, O.

AU - Morgan, K.

AU - Allen, M.

AU - Wilcox, S. L.

AU - Ma, L.

AU - Walker, L. P.

AU - Kouri, N.

AU - Burgess, J. D.

AU - Younkin, L. H.

AU - Younkin, Samuel G.

AU - Younkin, C. S.

AU - Bisceglio, G. D.

AU - Crook, Juliana

AU - Dickson, Dennis W

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Younkin, Steven G

AU - Taner, Nilufer

PY - 2010/2

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N2 - 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 ∼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 × 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. 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.

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