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PMID: 17434289 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimer's disease: patterns of linkage disequilibrium and disease/marker association.

Genomics ·Vol. 89 ·No. 6 ·2007-06-00 ·Pages 655-65

Yu CE, Seltman H, Peskind ER, Galloway N, Zhou PX, Rosenthal E, Wijsman EM, Tsuang DW, Devlin B, Schellenberg GD

Abstract

The epsilon(4) allele of APOE confers a two- to fourfold increased risk for late-onset Alzheimer's disease (LOAD), but LOAD pathology does not all fit neatly around APOE. It is conceivable that genetic variation proximate to APOE contributes to LOAD risk. Therefore, we investigated the degree of linkage disequilibrium (LD) for a comprehensive set of 50 SNPs in and surrounding APOE using a substantial Caucasian sample of 1100 chromosomes. SNPs in APOE were further molecularly haplotyped to determine their phases. One set of SNPs in TOMM40, roughly 15 kb upstream of APOE, showed intriguing LD with the epsilon(4) allele and was strongly associated with the risk for developing LOAD. However, when all the SNPs were entered into a logit model, only the effect of APOE epsilon(4) remained significant. These observations diminish the possibility that loci in the TOMM40 gene may have a major effect on the risk for LOAD in Caucasians.

MeSH Terms
Age of Onset Aged Alleles Alzheimer Disease/genetics Apolipoprotein E4/genetics Apolipoproteins E/genetics Case-Control Studies Chromosome Mapping Female Genetic Markers Haplotypes Humans Linkage Disequilibrium Male Membrane Transport Proteins/genetics Mitochondrial Precursor Protein Import Complex Proteins Polymorphism, Single Nucleotide Risk Factors Whites/genetics
Chemicals
Apolipoprotein E4 Apolipoproteins E Genetic Markers Membrane Transport Proteins Mitochondrial Precursor Protein Import Complex Proteins TOMM40 protein, human
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Yu Chang-En
Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA. changeyu@u.washington.edu
Seltman Howard
Peskind Elaine R
Galloway Nichole
Zhou Peter X
Rosenthal Elisabeth
Wijsman Ellen M
Tsuang Debby W
Devlin Bernie
Schellenberg Gerard D
References (50)
50 references, click to expand
  1. Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease.
    Neurogenetics. 2004 Dec;5(4):201-8 PMID: 15455263
  2. Gender- and age-specific contributions of additional DNA sequence variation in the 5' regulatory region of the APOE gene to prediction of measures of lipid metabolism.
    Hum Genet. 2004 Sep;115(4):331-45 PMID: 15300423
  3. Characterization of multilocus linkage disequilibrium.
    Genet Epidemiol. 2005 Apr;28(3):193-206 PMID: 15637716
  4. Dissection of the mitochondrial import and assembly pathway for human Tom40.
    J Biol Chem. 2005 Mar 25;280(12):11535-43 PMID: 15644312
  5. Neuronal specific regulatory elements in apolipoprotein E gene proximal promoter.
    Neuroreport. 2005 Jun 21;16(9):1027-30 PMID: 15931082
  6. Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease.
    Mol Psychiatry. 2005 Nov;10(11):1026-36 PMID: 16027741
  7. Accounting for linkage disequilibrium among markers in linkage analysis: impact of haplotype frequency estimation and molecular haplotypes for a gene in a candidate region for Alzheimer's disease.
    Hum Hered. 2007;63(1):26-34 PMID: 17215579
  8. Tree scanning: a method for using haplotype trees in phenotype/genotype association studies.
    Genetics. 2005 Jan;169(1):441-53 PMID: 15371364
  9. Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism.
    Am J Hum Genet. 2000 Oct;67(4):881-900 PMID: 10986041
  10. Duplicated downstream enhancers control expression of the human apolipoprotein E gene in macrophages and adipose tissue.
    J Biol Chem. 2000 Oct 13;275(41):31567-72 PMID: 10893248
  11. Effect of APOE genotype and promoter polymorphism on risk of Alzheimer's disease.
    Neurology. 2000 Dec 12;55(11):1644-9 PMID: 11113217
  12. The genetics of Alzheimer's disease.
    Curr Psychiatry Rep. 2000 Apr;2(2):158-64 PMID: 11122949
  13. Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain.
    J Neurosci. 2001 Feb 1;21(3):812-22 PMID: 11157067
  14. A new statistical method for haplotype reconstruction from population data.
    Am J Hum Genet. 2001 Apr;68(4):978-89 PMID: 11254454
  15. Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia?
    J Neurosci Res. 2001 Dec 1;66(5):851-6 PMID: 11746411
  16. Multiple-threshold models for genetic influences on age of onset for Alzheimer disease: findings in Swedish twins.
    Am J Med Genet. 2001 Dec 8;105(8):724-8 PMID: 11803520
  17. The Th1/E47cs-G apolipoprotein E (APOE) promoter allele is a risk factor for Alzheimer disease of very later onset.
    Neurosci Lett. 2002 Jul 5;326(3):187-90 PMID: 12095653
  18. Contribution of APOE promoter polymorphisms to Alzheimer's disease risk.
    Neurology. 2002 Jul 9;59(1):59-66 PMID: 12105308
  19. High-resolution genetic mapping of the ACE-linked QTL influencing circulating ACE activity.
    Eur J Hum Genet. 2002 Sep;10(9):553-61 PMID: 12173033
  20. Contributions of 18 additional DNA sequence variations in the gene encoding apolipoprotein E to explaining variation in quantitative measures of lipid metabolism.
    Am J Hum Genet. 2002 Sep;71(3):501-17 PMID: 12165926
  21. Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription.
    J Neurochem. 2003 Mar;84(6):1215-36 PMID: 12614323
  22. Tom40, the import channel of the mitochondrial outer membrane, plays an active role in sorting imported proteins.
    EMBO J. 2003 May 15;22(10):2380-6 PMID: 12743032
  23. Evolutionary-based association analysis using haplotype data.
    Genet Epidemiol. 2003 Jul;25(1):48-58 PMID: 12813726
  24. Neurotoxic mechanisms caused by the Alzheimer's disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway.
    J Biol Chem. 2003 Jul 25;278(30):28294-302 PMID: 12730216
  25. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.
    Am J Hum Genet. 2004 Jan;74(1):106-20 PMID: 14681826
  26. Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data.
    Genetics. 2003 Dec;165(4):2213-33 PMID: 14704198
  27. Identification of a novel enhancer of brain expression near the apoE gene cluster by comparative genomics.
    Biochim Biophys Acta. 2004 Jan 5;1676(1):41-50 PMID: 14732489
  28. Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage.
    Neuromolecular Med. 2004;5(2):147-62 PMID: 15075441
  29. ApoE genotype accounts for the vast majority of AD risk and AD pathology.
    Neurobiol Aging. 2004 May-Jun;25(5):641-50 PMID: 15172743
  30. Further investigation of linkage disequilibrium SNPs and their ability to identify associated susceptibility loci.
    Ann Hum Genet. 2004 May;68(Pt 3):240-8 PMID: 15180704
  31. Evidence for substantial fine-scale variation in recombination rates across the human genome.
    Nat Genet. 2004 Jul;36(7):700-6 PMID: 15184900
  32. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease.
    Ann Intern Med. 2004 Jul 20;141(2):137-47 PMID: 15262670
  33. ADLAPH: A molecular haplotyping method based on allele-discriminating long-range PCR.
    Genomics. 2004 Sep;84(3):600-12 PMID: 15498468
  34. A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. I. Basic theory and an analysis of alcohol dehydrogenase activity in Drosophila.
    Genetics. 1987 Oct;117(2):343-51 PMID: 2822535
  35. Expression of 'Alzheimer antigens' in cultured skin fibroblasts.
    Arch Neurol. 1991 Jul;48(7):709-17 PMID: 1859298
  36. A far-downstream hepatocyte-specific control region directs expression of the linked human apolipoprotein E and C-I genes in transgenic mice.
    J Biol Chem. 1993 Apr 15;268(11):8221-9 PMID: 7681840
  37. Empirical tests of some predictions from coalescent theory with applications to intraspecific phylogeny reconstruction.
    Genetics. 1993 Jul;134(3):959-69 PMID: 8349118
  38. Localization of a liver-specific enhancer in the apolipoprotein E/C-I/C-II gene locus.
    J Lipid Res. 1993 Oct;34(10):1699-707 PMID: 8245720
  39. Arginine residues at codons 112 and 158 in the apolipoprotein E gene correspond to the ancestral state in humans.
    Atherosclerosis. 1995 Jan 6;112(1):85-90 PMID: 7772071
  40. A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping or DNA sequencing. V. Analysis of case/control sampling designs: Alzheimer's disease and the apoprotein E locus.
    Genetics. 1995 May;140(1):403-9 PMID: 7635303
  41. A comparison of linkage disequilibrium measures for fine-scale mapping.
    Genomics. 1995 Sep 20;29(2):311-22 PMID: 8666377
  42. Disequilibrium mapping: composite likelihood for pairwise disequilibrium.
    Genomics. 1996 Aug 15;36(1):1-16 PMID: 8812410
  43. Association between common alleles of the low-density lipoprotein receptor gene region and interindividual variation in plasma lipid and apolipoprotein levels in a population-based sample from Rochester, Minnesota.
    Hum Genet. 1997 Jan;99(1):108-14 PMID: 9003506
  44. 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.
    JAMA. 1997 Oct 22-29;278(16):1349-56 PMID: 9343467
  45. A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia.
    Nat Genet. 1998 Jan;18(1):69-71 PMID: 9425904
  46. Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene.
    FEBS Lett. 1998 Jan 9;421(2):105-8 PMID: 9468288
  47. Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease.
    Hum Mol Genet. 1998 Sep;7(9):1511-6 PMID: 9700208
  48. Measured haplotype analysis of the angiotensin-I converting enzyme gene.
    Hum Mol Genet. 1998 Oct;7(11):1745-51 PMID: 9736776
  49. The -491A/T apolipoprotein E promoter polymorphism association with Alzheimer's disease: independent risk and linkage disequilibrium with the known APOE polymorphism.
    Neurosci Lett. 1998 Aug 14;252(2):95-8 PMID: 9756330
  50. Prospects for whole-genome linkage disequilibrium mapping of common disease genes.
    Nat Genet. 1999 Jun;22(2):139-44 PMID: 10369254
Article Info
Journal
Genomics
Abbr.
Genomics
ISSN
0888-7543
DOI
10.1016/j.ygeno.2007.02.002
Email
changeyu@u.washington.edu
Published
2007-06-00
Epub
2007-00-16
Pages
655-65
Language
English
Region
United States
NLM ID
8800135
PMCID
PMC1978251
Subset
IM
Grants
NIMH NIH HHS · MH57881 · United States
NIA NIH HHS · R21 AG024486-01 · United States
NIMH NIH HHS · R37 MH057881 · United States
NIA NIH HHS · U24 AG021886 · United States
NIA NIH HHS · P50 AG005136-21 · United States
NIA NIH HHS · R01 AG021544-05 · United States
NIMH NIH HHS · R01 MH057881 · United States
NIA NIH HHS · P50 AG005136 · United States
NIA NIH HHS · AG21544 · United States
NIA NIH HHS · R21 AG024486 · United States
NIA NIH HHS · P50 AG005136-23 · United States
NIA NIH HHS · AG05136 · United States
NIA NIH HHS · R01 AG021544 · United States
NIA NIH HHS · R21 AG024486-02 · United States
NIA NIH HHS · AG24486 · United States
External Links
PubMed source DOI: 10.1016/j.ygeno.2007.02.002 PMC Full Text View journal details
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