Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease.

BACKGROUND Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene. OBJECTIVE To attempt to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset. DESIGN We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue. SETTING Alzheimer's Disease Research Center. PARTICIPANTS Research volunteers who were cognitively normal or had Alzheimer disease. MAIN OUTCOME MEASURES Disease status and age at onset. RESULTS We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or β-amyloid 42 levels or TOMM40 or APOE gene expression. CONCLUSIONS Although we did not replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study.

[1]  Thomas W. Mühleisen,et al.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease , 2013, Nature Genetics.

[2]  A. Fagan,et al.  Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. , 2007, Archives of neurology.

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

[4]  A. Fagan,et al.  Extreme cerebrospinal fluid amyloid β levels identify family with late‐onset Alzheimer's disease presenilin 1 mutation , 2007, Annals of neurology.

[5]  M. Gill,et al.  Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants. , 2007, Human molecular genetics.

[6]  Eden R Martin,et al.  Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. , 2009, American journal of human genetics.

[7]  A. Fagan,et al.  Validating predicted biological effects of Alzheimer's disease associated SNPs using CSF biomarker levels. , 2010, Journal of Alzheimer's disease : JAD.

[8]  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.

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

[10]  Ellen M Wijsman,et al.  Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimer's disease: patterns of linkage disequilibrium and disease/marker association. , 2007, Genomics.

[11]  A D Roses,et al.  A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease , 2009, The Pharmacogenomics Journal.

[12]  Andrey Alexeyenko,et al.  Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease , 2010, Journal of Human Genetics.

[13]  M Krawczak,et al.  Examination of the current top candidate genes for AD in a genome-wide association study , 2010, Molecular Psychiatry.

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

[15]  Gina N. LaRossa,et al.  Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans , 2006, Annals of neurology.

[16]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease: Report of the NINCDS—ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease , 2011, Neurology.

[17]  A. Fagan,et al.  SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease , 2010, PLoS genetics.

[18]  Peter Imle,et al.  Fluorescence-based fragment size analysis. , 2005, Methods in molecular biology.

[19]  A. Fagan,et al.  Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition , 2008, Proceedings of the National Academy of Sciences.

[20]  M. Cuccaro,et al.  Multiple rare SAPAP3 missense variants in trichotillomania and OCD , 2009, Molecular Psychiatry.

[21]  V. Pankratz,et al.  Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease , 2009, Nature Genetics.

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

[23]  K. Lunetta,et al.  Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. , 2010, Archives of neurology.

[24]  Christoph Lange,et al.  Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. , 2008, American journal of human genetics.

[25]  Peter Donnelly,et al.  A comparison of bayesian methods for haplotype reconstruction from population genotype data. , 2003, American journal of human genetics.

[26]  April N. Allen,et al.  Genome-Wide Association Study for Alzheimer's Disease Risk in a Large Cohort Of Clinically Characterized And Neuropathologically Verified Subjects , 2010, Alzheimer's & Dementia.

[27]  J. Price,et al.  Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. , 1998, Archives of neurology.

[28]  R. Petersen,et al.  Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects , 2009, Annals of neurology.

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