A TOMM40 Variable-length Polymorphism Predicts the Age of Late-onset Alzheimer's Disease

Overview

Journal Pharmacogenomics J

Specialties Genetics
Molecular Biology
Pharmacology

Date 2009 Dec 24

PMID 20029386

Citations 206

Authors

A D Roses

M W Lutz

H Amrine-Madsen

A M Saunders

D G Crenshaw

S S Sundseth

M J Huentelman

K A Welsh-Bohmer

E M Reiman

Affiliations

Soon will be listed here.

Abstract

The ɛ4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE ɛ3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE ɛ3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE ɛ3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ɛ3 (70.5 ± 1.2 years versus 77.6 ± 2.1 years, P=0.02, n=34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases.

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References

Swami M, Hendricks A, Gillis T, Massood T, Mysore J, Myers R . Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset. Hum Mol Genet. 2009; 18(16):3039-47. PMC: 2714728. DOI: 10.1093/hmg/ddp242. View

Devi L, Prabhu B, Galati D, Avadhani N, Anandatheerthavarada H . Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006; 26(35):9057-68. PMC: 6675337. DOI: 10.1523/JNEUROSCI.1469-06.2006. View

Cummings C, Zoghbi H . Fourteen and counting: unraveling trinucleotide repeat diseases. Hum Mol Genet. 2000; 9(6):909-16. DOI: 10.1093/hmg/9.6.909. View

Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan M . Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am J Hum Genet. 2008; 83(5):623-32. PMC: 2668052. DOI: 10.1016/j.ajhg.2008.10.008. View

Park K, Goto K . A review of the benefit-risk profile of gefitinib in Asian patients with advanced non-small-cell lung cancer. Curr Med Res Opin. 2006; 22(3):561-73. DOI: 10.1185/030079906X89847. View

Corder E, Saunders A, Strittmatter W, Schmechel D, Gaskell P, Small G . Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993; 261(5123):921-3. DOI: 10.1126/science.8346443. View

Goldstein D . Common genetic variation and human traits. N Engl J Med. 2009; 360(17):1696-8. DOI: 10.1056/NEJMp0806284. View

Takei N, Miyashita A, Tsukie T, Arai H, Asada T, Imagawa M . Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese. Genomics. 2009; 93(5):441-8. DOI: 10.1016/j.ygeno.2009.01.003. View

Li H, Wetten S, Li L, St Jean P, Upmanyu R, Surh L . Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2007; 65(1):45-53. DOI: 10.1001/archneurol.2007.3. View

10.

Pericak-Vance M, Bebout J, Gaskell Jr P, Yamaoka L, Hung W, Alberts M . Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet. 1991; 48(6):1034-50. PMC: 1683100. View

11.

Potkin S, Guffanti G, Lakatos A, Turner J, Kruggel F, Fallon J . Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's disease. PLoS One. 2009; 4(8):e6501. PMC: 2719581. DOI: 10.1371/journal.pone.0006501. View

12.

Jiang H . Overview of gefitinib in non-small cell lung cancer: an Asian perspective. Jpn J Clin Oncol. 2008; 39(3):137-50. DOI: 10.1093/jjco/hyn139. View

13.

Lai E, Riley J, Purvis I, Roses A . A 4-Mb high-density single nucleotide polymorphism-based map around human APOE. Genomics. 1998; 54(1):31-8. DOI: 10.1006/geno.1998.5581. View

14.

Beecham G, Martin E, Li Y, Slifer M, Gilbert J, Haines J . Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet. 2009; 84(1):35-43. PMC: 2668056. DOI: 10.1016/j.ajhg.2008.12.008. View

15.

Tachmazidou I, Verzilli C, De Iorio M . Genetic association mapping via evolution-based clustering of haplotypes. PLoS Genet. 2007; 3(7):e111. PMC: 1913101. DOI: 10.1371/journal.pgen.0030111. View

16.

. 2008 Alzheimer's disease facts and figures. Alzheimers Dement. 2008; 4(2):110-33. DOI: 10.1016/j.jalz.2008.02.005. View

17.

Anandatheerthavarada H, Biswas G, Robin M, Avadhani N . Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol. 2003; 161(1):41-54. PMC: 2172865. DOI: 10.1083/jcb.200207030. View

18.

Risner M, Saunders A, Altman J, Ormandy G, Craft S, Foley I . Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 2006; 6(4):246-54. DOI: 10.1038/sj.tpj.6500369. View

19.

Librado P, Rozas J . DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics. 2009; 25(11):1451-2. DOI: 10.1093/bioinformatics/btp187. View

20.

Atamna H, Frey 2nd W . Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer's disease. Mitochondrion. 2007; 7(5):297-310. DOI: 10.1016/j.mito.2007.06.001. View