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

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 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 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.

[1]  J. Ioannidis,et al.  Evaluation of the potential excess of statistically significant findings in published genetic association studies: application to Alzheimer's disease. , 2008, American journal of epidemiology.

[2]  Eden R Martin,et al.  Confronting complexity in late‐onset Alzheimer disease: application of two‐stage analysis approach addressing heterogeneity and epistasis , 2008, Genetic epidemiology.

[3]  K. Mossman.  The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[4]  A. J. Slater,et al.  Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. , 2008, Archives of neurology.

[5]  Winnie S. Liang,et al.  GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers , 2007, Neuron.

[6]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[7]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[8]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[9]  Rebecca F. Halperin,et al.  A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. , 2007, The Journal of clinical psychiatry.

[10]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[11]  Winnie S. Liang,et al.  GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. , 2007, Neuron.

[12]  J. Hardy.  Does Abeta 42 have a function related to blood homeostasis? , 2007, Neurochemical research.

[13]  D. Blacker,et al.  Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database , 2007, Nature Genetics.

[14]  Edward R. Dougherty,et al.  SNiPer-HD: improved genotype calling accuracy by an expectation-maximization algorithm for high-density SNP arrays , 2007, Bioinform..

[15]  J. Hardy.  Does Aβ 42 Have a Function Related to Blood Homeostasis? , 2007, Neurochemical Research.

[16]  Jonathan Stone,et al.  Microvascular pathology in the aging human brain: Evidence that senile plaques are sites of microhaemorrhages , 2006, Neurobiology of Aging.

[17]  D. Connor,et al.  Circle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles , 2006, Acta Neuropathologica.

[18]  Kaj Blennow,et al.  Towards compendia of negative genetic association studies: an example for Alzheimer disease , 2006, Human Genetics.

[19]  Qiong Yang,et al.  Power and type I error rate of false discovery rate approaches in genome-wide association studies , 2005, BMC Genetics.

[20]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[21]  R. Fernando,et al.  Controlling the Proportion of False Positives in Multiple Dependent Tests , 2004, Genetics.

[22]  Thomas G. Beach,et al.  Circle of Willis Atherosclerosis Is a Risk Factor for Sporadic Alzheimer’s Disease , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[23]  J. Houwing-Duistermaat,et al.  Angiotensin-Converting Enzyme Gene Polymorphism and Carotid Artery Wall Thickness: A Meta-Analysis , 2003, Stroke.

[24]  E. Lander,et al.  Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease , 2003, Nature Genetics.

[25]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[26]  A. Adeyemo,et al.  Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides. , 2002, Human molecular genetics.

[27]  J Blangero,et al.  Large upward bias in estimation of locus-specific effects from genomewide scans. , 2001, American journal of human genetics.

[28]  J Tuomilehto,et al.  Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study , 2001, BMJ.

[29]  C Gu,et al.  False positives and false negatives in genome scans. , 2001, Advances in genetics.

[30]  P. Donnelly,et al.  Inference of population structure using multilocus genotype data. , 2000, Genetics.

[31]  R. Havlik,et al.  Midlife blood pressure and dementia: the Honolulu–Asia aging study☆ , 2000, Neurobiology of Aging.

[32]  M. Owen,et al.  Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease , 1999, Nature Genetics.

[33]  J. Staessen,et al.  The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular‐renal risk , 1997, Journal of hypertension.

[34]  J. Haines,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. , 1997, JAMA.

[35]  A. Hofman,et al.  Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study , 1997, The Lancet.

[36]  D C Rao,et al.  Trade‐off between false positives and false negatives in the linkage analysis of complex traits , 1997, Genetic epidemiology.

[37]  A. D. Roses,et al.  Association of apolipoprotein E allele €4 with late-onset familial and sporadic Alzheimer’s disease , 2006 .

[38]  M A Pericak-Vance,et al.  Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. , 1993, Neurology.

[39]  P Corvol,et al.  An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. , 1990, The Journal of clinical investigation.