Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from meta-analysis

Jennifer Webster, Eric M. Reiman, Victoria L. Zismann, Keta D. Joshipura, John V. Pearson, Diane Hu-Lince, Matthew J. Huentelman, David W. Craig, Keith D. Coon, Thomas Beach, Kristen C. Rohrer, Alice S. Zhao, Doris Leung, Leslie Bryden, Lauren Marlowe, Mona Kaleem, Diego Mastroeni, Andrew Grover, Joseph Rogers, Reinhard HeunFrank Jessen, Heike Kölsch, Christopher B. Heward, Rivka Ravid, Michael L. Hutton, Stacey Melquist, Ron C. Petersen, Richard J. Caselli, Andreas Papassotiropoulos, Dietrich A. Stephan, John Hardy, Amanda J Myers

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1st, 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathologically verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 "top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected pvalue=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (pvalue=0.03). We present the results of our ACE replication along with a discussion of the statistical limitations of multiple test corrections in whole genome studies.

Original languageEnglish
Pages (from-to)19-30
Number of pages12
JournalInternational Journal of Molecular Epidemiology and Genetics
Volume1
Issue number1
StatePublished - Jul 21 2010

Fingerprint

Genome-Wide Association Study
Peptidyl-Dipeptidase A
Single Nucleotide Polymorphism
Meta-Analysis
Alzheimer Disease
Apolipoproteins E
Genome
Chromosomes, Human, Pair 19
Genetic Association Studies
Proxy
Odds Ratio
Databases
Confidence Intervals
Research
Genes

Keywords

  • ACE
  • Genome-wide association study
  • Late-onset alzheimer disease
  • Metaanalysis
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Genetics

Cite this

Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from meta-analysis. / Webster, Jennifer; Reiman, Eric M.; Zismann, Victoria L.; Joshipura, Keta D.; Pearson, John V.; Hu-Lince, Diane; Huentelman, Matthew J.; Craig, David W.; Coon, Keith D.; Beach, Thomas; Rohrer, Kristen C.; Zhao, Alice S.; Leung, Doris; Bryden, Leslie; Marlowe, Lauren; Kaleem, Mona; Mastroeni, Diego; Grover, Andrew; Rogers, Joseph; Heun, Reinhard; Jessen, Frank; Kölsch, Heike; Heward, Christopher B.; Ravid, Rivka; Hutton, Michael L.; Melquist, Stacey; Petersen, Ron C.; Caselli, Richard J.; Papassotiropoulos, Andreas; Stephan, Dietrich A.; Hardy, John; Myers, Amanda J.

In: International Journal of Molecular Epidemiology and Genetics, Vol. 1, No. 1, 21.07.2010, p. 19-30.

Research output: Contribution to journalArticle

Webster, J, Reiman, EM, Zismann, VL, Joshipura, KD, Pearson, JV, Hu-Lince, D, Huentelman, MJ, Craig, DW, Coon, KD, Beach, T, Rohrer, KC, Zhao, AS, Leung, D, Bryden, L, Marlowe, L, Kaleem, M, Mastroeni, D, Grover, A, Rogers, J, Heun, R, Jessen, F, Kölsch, H, Heward, CB, Ravid, R, Hutton, ML, Melquist, S, Petersen, RC, Caselli, RJ, Papassotiropoulos, A, Stephan, DA, Hardy, J & Myers, AJ 2010, 'Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from meta-analysis', International Journal of Molecular Epidemiology and Genetics, vol. 1, no. 1, pp. 19-30.
Webster, Jennifer ; Reiman, Eric M. ; Zismann, Victoria L. ; Joshipura, Keta D. ; Pearson, John V. ; Hu-Lince, Diane ; Huentelman, Matthew J. ; Craig, David W. ; Coon, Keith D. ; Beach, Thomas ; Rohrer, Kristen C. ; Zhao, Alice S. ; Leung, Doris ; Bryden, Leslie ; Marlowe, Lauren ; Kaleem, Mona ; Mastroeni, Diego ; Grover, Andrew ; Rogers, Joseph ; Heun, Reinhard ; Jessen, Frank ; Kölsch, Heike ; Heward, Christopher B. ; Ravid, Rivka ; Hutton, Michael L. ; Melquist, Stacey ; Petersen, Ron C. ; Caselli, Richard J. ; Papassotiropoulos, Andreas ; Stephan, Dietrich A. ; Hardy, John ; Myers, Amanda J. / Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from meta-analysis. In: International Journal of Molecular Epidemiology and Genetics. 2010 ; Vol. 1, No. 1. pp. 19-30.
@article{425eeb3080f540b2ba4b43741eef9c2e,
title = "Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from meta-analysis",
abstract = "For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1st, 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathologically verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 {"}top AlzGenes{"}, 32 SNPs in 24 genes had odds ratios (OR) whose 95{\%} confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80{\%} power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected pvalue=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (pvalue=0.03). We present the results of our ACE replication along with a discussion of the statistical limitations of multiple test corrections in whole genome studies.",
keywords = "ACE, Genome-wide association study, Late-onset alzheimer disease, Metaanalysis, Single nucleotide polymorphism",
author = "Jennifer Webster and Reiman, {Eric M.} and Zismann, {Victoria L.} and Joshipura, {Keta D.} and Pearson, {John V.} and Diane Hu-Lince and Huentelman, {Matthew J.} and Craig, {David W.} and Coon, {Keith D.} and Thomas Beach and Rohrer, {Kristen C.} and Zhao, {Alice S.} and Doris Leung and Leslie Bryden and Lauren Marlowe and Mona Kaleem and Diego Mastroeni and Andrew Grover and Joseph Rogers and Reinhard Heun and Frank Jessen and Heike K{\"o}lsch and Heward, {Christopher B.} and Rivka Ravid and Hutton, {Michael L.} and Stacey Melquist and Petersen, {Ron C.} and Caselli, {Richard J.} and Andreas Papassotiropoulos and Stephan, {Dietrich A.} and John Hardy and Myers, {Amanda J}",
year = "2010",
month = "7",
day = "21",
language = "English",
volume = "1",
pages = "19--30",
journal = "International Journal of Molecular Epidemiology and Genetics",
issn = "1948-1756",
publisher = "e-Century Publishing Corporation",
number = "1",

}

TY - JOUR

T1 - Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from meta-analysis

AU - Webster, Jennifer

AU - Reiman, Eric M.

AU - Zismann, Victoria L.

AU - Joshipura, Keta D.

AU - Pearson, John V.

AU - Hu-Lince, Diane

AU - Huentelman, Matthew J.

AU - Craig, David W.

AU - Coon, Keith D.

AU - Beach, Thomas

AU - Rohrer, Kristen C.

AU - Zhao, Alice S.

AU - Leung, Doris

AU - Bryden, Leslie

AU - Marlowe, Lauren

AU - Kaleem, Mona

AU - Mastroeni, Diego

AU - Grover, Andrew

AU - Rogers, Joseph

AU - Heun, Reinhard

AU - Jessen, Frank

AU - Kölsch, Heike

AU - Heward, Christopher B.

AU - Ravid, Rivka

AU - Hutton, Michael L.

AU - Melquist, Stacey

AU - Petersen, Ron C.

AU - Caselli, Richard J.

AU - Papassotiropoulos, Andreas

AU - Stephan, Dietrich A.

AU - Hardy, John

AU - Myers, Amanda J

PY - 2010/7/21

Y1 - 2010/7/21

N2 - For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1st, 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathologically verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 "top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected pvalue=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (pvalue=0.03). We present the results of our ACE replication along with a discussion of the statistical limitations of multiple test corrections in whole genome studies.

AB - For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1st, 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathologically verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 "top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected pvalue=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (pvalue=0.03). We present the results of our ACE replication along with a discussion of the statistical limitations of multiple test corrections in whole genome studies.

KW - ACE

KW - Genome-wide association study

KW - Late-onset alzheimer disease

KW - Metaanalysis

KW - Single nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=77954641948&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954641948&partnerID=8YFLogxK

M3 - Article

C2 - 21537449

AN - SCOPUS:77954641948

VL - 1

SP - 19

EP - 30

JO - International Journal of Molecular Epidemiology and Genetics

JF - International Journal of Molecular Epidemiology and Genetics

SN - 1948-1756

IS - 1

ER -