Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals.

In this study, we assess 34 of the most replicated genetic associations for Alzheimer's disease (AD) using data generated on Affymetrix SNP 6.0 arrays and imputed at over 5.7 million markers from a unique cohort of over 1600 neuropathologically defined AD cases and controls (1019 cases and 591 controls). Testing the top genes from the AlzGene meta-analysis, we confirm the well-known association with APOE single nucleotide polymorphisms (SNPs), the CLU, PICALM and CR1 SNPs recently implicated in unusually large data sets, and previously implicated CST3 and ACE SNPs. In the cases of CLU, PICALM and CR1, as well as in APOE, the odds ratios we find are slightly larger than those previously reported in clinical samples, consistent with what we believe to be more accurate classification of disease in the clinically characterized and neuropathologically confirmed AD cases and controls.

[1]  J. Williamson,et al.  Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. , 2009, Archives of internal medicine.

[2]  T. Weaver,et al.  Miniaturized sealed‐tube allele‐specific PCR , 2002, Human mutation.

[3]  Woodrow D. Deitrich,et al.  The National Alzheimer's Coordinating Center (NACC) Database: An Alzheimer Disease Database , 2004, Alzheimer disease and associated disorders.

[4]  M. Albert,et al.  Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. , 1989, JAMA.

[5]  A. Hofman,et al.  Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. , 1998, Archives of neurology.

[6]  Joshua M. Korn,et al.  Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs , 2008, Nature Genetics.

[7]  W. Noble,et al.  Linking Amyloid and Tau Pathology in Alzheimer's Disease: The Role of Membrane Cholesterol in Aβ-Mediated Tau Toxicity , 2009, The Journal of Neuroscience.

[8]  John Hardy,et al.  Single-day apolipoprotein E genotyping , 1994, Journal of Neuroscience Methods.

[9]  Nick C Fox,et al.  Letter abstract - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's Disease , 2009 .

[10]  Jennifer Williamson,et al.  Genetic Aspects of Alzheimer Disease , 2009, The neurologist.

[11]  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.

[12]  P. Bosco,et al.  Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease , 2009, Nature Genetics.

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

[14]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[15]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[16]  M. Michikawa.  Neurodegenerative disorders and cholesterol. , 2004, Current Alzheimer research.

[17]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[18]  D. Radvinsky,et al.  Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models. , 2007, Nature genetics.

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

[20]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[21]  Nick C Fox,et al.  Genetic Variability in CLU and Its Association with Alzheimer's Disease , 2010, PloS one.

[22]  E M Wijsman,et al.  The number of trait loci in late-onset Alzheimer disease. , 2000, American journal of human genetics.

[23]  David A. Bennett,et al.  Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles , 2009, Neurology.

[24]  H. Christensen,et al.  Risk Factors of Transition from Normal Cognition to Mild Cognitive Disorder: The PATH through Life Study , 2009, Dementia and Geriatric Cognitive Disorders.

[25]  M. Albert,et al.  Apolipoprotein E epsilon4 and incidence of Alzheimer disease in a community population of older persons. , 1997, Journal of the American Medical Association (JAMA).

[26]  B. Winblad,et al.  Apolipoprotein E genotypes and the incidence of Alzheimer's disease among persons aged 75 years and older: variation by use of antihypertensive medication? , 2001, American journal of epidemiology.

[27]  D. Stephan,et al.  Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from Meta-analysis. , 2010, International journal of molecular epidemiology and genetics.

[28]  D. Stephan,et al.  Genetic control of human brain transcript expression in Alzheimer disease. , 2009, American journal of human genetics.

[29]  David H. Alexander,et al.  Fast model-based estimation of ancestry in unrelated individuals. , 2009, Genome research.

[30]  V. Hachinski,et al.  Hypertension, executive dysfunction, and progression to dementia: the canadian study of health and aging. , 2010, Archives of neurology.

[31]  H. Braak,et al.  Staging of alzheimer's disease-related neurofibrillary changes , 1995, Neurobiology of Aging.

[32]  J. Ashford,et al.  Non-familial Alzheimer's disease is mainly due to genetic factors. , 2002, Journal of Alzheimer's disease : JAD.

[33]  J. Meyer,et al.  Multiple threshold model for the onset of Alzheimer's disease in the NAS-NRC twin panel. , 1998, American journal of medical genetics.

[34]  D. Stephan,et al.  A survey of genetic human cortical gene expression , 2007, Nature Genetics.

[35]  L. Kiemeney,et al.  Corrigendum: Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer , 2009, Nature Genetics.

[36]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

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