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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 1(st), 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy 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 ?=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 p-value=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 (p-value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies.

SUBMITTER: Webster J

PROVIDER: S-EPMC3076748 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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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 J Reiman Eric M EM Zismann Victoria L VL Joshipura Keta D KD Pearson John V JV Hu-Lince Diane D Huentelman Matthew J MJ Craig David W DW Coon Keith D KD Beach Thomas T Rohrer Kristen C KC Zhao Alice S AS Leung Doris D Bryden Leslie L Marlowe Lauren L Kaleem Mona M Mastroeni Diego D Grover Andrew A Rogers Joseph J Heun Reinhard R Jessen Frank F Kölsch Heike H Heward Christopher B CB Ravid Rivka R Hutton Michael L ML Melquist Stacey S Petersen Ron C RC Caselli Richard J RJ Papassotiropoulos Andreas A Stephan Dietrich A DA Hardy John J Myers Amanda A

International journal of molecular epidemiology and genetics 20090726 1

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 1(st), 2007 were investigated in our whole genome association data set consisting of 1411 LOA ...[more]

PMID: 21537449

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Project description:BackgroundVaccine protection investigation includes three processes: vaccination, pathogen challenge, and vaccine protection efficacy assessment. Many variables can affect the results of vaccine protection. Brucella, a genus of facultative intracellular bacteria, is the etiologic agent of brucellosis in humans and multiple animal species. Extensive research has been conducted in developing effective live attenuated Brucella vaccines. We hypothesized that some variables play a more important role than others in determining vaccine protective efficacy. Using Brucella vaccines and vaccine candidates as study models, this hypothesis was tested by meta-analysis of Brucella vaccine studies reported in the literature.ResultsNineteen variables related to vaccine-induced protection of mice against infection with virulent brucellae were selected based on modeling investigation of the vaccine protection processes. The variable "vaccine protection efficacy" was set as a dependent variable while the other eighteen were set as independent variables. Discrete or continuous values were collected from papers for each variable of each data set. In total, 401 experimental groups were manually annotated from 74 peer-reviewed publications containing mouse protection data for live attenuated Brucella vaccines or vaccine candidates. Our ANOVA analysis indicated that nine variables contributed significantly (P-value < 0.05) to Brucella vaccine protection efficacy: vaccine strain, vaccination host (mouse) strain, vaccination dose, vaccination route, challenge pathogen strain, challenge route, challenge-killing interval, colony forming units (CFUs) in mouse spleen, and CFU reduction compared to control group. The other 10 variables (e.g., mouse age, vaccination-challenge interval, and challenge dose) were not found to be statistically significant (P-value > 0.05). The protection level of RB51 was sacrificed when the values of several variables (e.g., vaccination route, vaccine viability, and challenge pathogen strain) change. It is suggestive that it is difficult to protect against aerosol challenge. Somewhat counter-intuitively, our results indicate that intraperitoneal and subcutaneous vaccinations are much more effective to protect against aerosol Brucella challenge than intranasal vaccination.ConclusionsLiterature meta-analysis identified variables that significantly contribute to Brucella vaccine protection efficacy. The results obtained provide critical information for rational vaccine study design. Literature meta-analysis is generic and can be applied to analyze variables critical for vaccine protection against other infectious diseases.

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

Publications

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

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