Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort

S. Kim, S. Swaminathan, Li Shen, S. L. Risacher, Kwangsik Nho, Tatiana Foroud, L. M. Shaw, J. Q. Trojanowski, S. G. Potkin, M. J. Huentelman, D. W. Craig, B. M. Dechairo, P. S. Aisen, R. C. Petersen, M. W. Weiner, Andrew Saykin

Research output: Contribution to journalArticle

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Abstract

Objectives: CSF levels of Aβ1-42, t-tau, and p-tau 181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (1-42, t-tau, p-tau181p, p-tau181p/Aβ1-42, and t-tau/Aβ1-42). Methods: A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuromaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p < 0.01 (uncorrected p < 3.10 x 10-8) and secondarily examined SNPs with uncorrected p values less than 10-5 to identify potential candidates. Results: Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates. Conclusions: In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.

Original languageEnglish
Pages (from-to)69-79
Number of pages11
JournalNeurology
Volume76
Issue number1
DOIs
StatePublished - Jan 4 2011

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Genome-Wide Association Study
Single Nucleotide Polymorphism
Biomarkers
Genes
Alzheimer Disease
Genome
Macrophage Colony-Stimulating Factor
Genetic Models
Genotype

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort. / Kim, S.; Swaminathan, S.; Shen, Li; Risacher, S. L.; Nho, Kwangsik; Foroud, Tatiana; Shaw, L. M.; Trojanowski, J. Q.; Potkin, S. G.; Huentelman, M. J.; Craig, D. W.; Dechairo, B. M.; Aisen, P. S.; Petersen, R. C.; Weiner, M. W.; Saykin, Andrew.

In: Neurology, Vol. 76, No. 1, 04.01.2011, p. 69-79.

Research output: Contribution to journalArticle

Kim, S, Swaminathan, S, Shen, L, Risacher, SL, Nho, K, Foroud, T, Shaw, LM, Trojanowski, JQ, Potkin, SG, Huentelman, MJ, Craig, DW, Dechairo, BM, Aisen, PS, Petersen, RC, Weiner, MW & Saykin, A 2011, 'Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort', Neurology, vol. 76, no. 1, pp. 69-79. https://doi.org/10.1212/WNL.0b013e318204a397
Kim, S. ; Swaminathan, S. ; Shen, Li ; Risacher, S. L. ; Nho, Kwangsik ; Foroud, Tatiana ; Shaw, L. M. ; Trojanowski, J. Q. ; Potkin, S. G. ; Huentelman, M. J. ; Craig, D. W. ; Dechairo, B. M. ; Aisen, P. S. ; Petersen, R. C. ; Weiner, M. W. ; Saykin, Andrew. / Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort. In: Neurology. 2011 ; Vol. 76, No. 1. pp. 69-79.
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AU - Swaminathan, S.

AU - Shen, Li

AU - Risacher, S. L.

AU - Nho, Kwangsik

AU - Foroud, Tatiana

AU - Shaw, L. M.

AU - Trojanowski, J. Q.

AU - Potkin, S. G.

AU - Huentelman, M. J.

AU - Craig, D. W.

AU - Dechairo, B. M.

AU - Aisen, P. S.

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N2 - Objectives: CSF levels of Aβ1-42, t-tau, and p-tau 181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (1-42, t-tau, p-tau181p, p-tau181p/Aβ1-42, and t-tau/Aβ1-42). Methods: A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuromaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p < 0.01 (uncorrected p < 3.10 x 10-8) and secondarily examined SNPs with uncorrected p values less than 10-5 to identify potential candidates. Results: Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates. Conclusions: In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.

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