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Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative

  • Allison A. Dilliott (a1) (a2), Emily C. Evans (a3), Sali M.K. Farhan (a4), Mahdi Ghani (a5), Christine Sato (a5), Ming Zhang (a5), Adam D. McIntyre (a1), Henian Cao (a1), Lemuel Racacho (a6) (a7), John F. Robinson (a1), Michael J. Strong (a1) (a8), Mario Masellis (a9) (a10), Dennis E. Bulman (a6) (a7), Ekaterina Rogaeva (a5), Sandra E. Black (a9) (a11), Elizabeth Finger (a8) (a12), Andrew Frank (a13), Morris Freedman (a10) (a14) (a15), Ayman Hassan (a16), Anthony Lang (a10) (a17), Christen L. Shoesmith (a8), Richard H. Swartz (a9), David Tang-Wai (a10) (a18), Maria Carmela Tartaglia (a5) (a10), John Turnbull (a19), Lorne Zinman (a9), the ONDRI Investigators (a1) (a2) (a3) (a4) (a5) (a6) (a7) (a8) (a9) (a10) (a11) (a12) (a13) (a14) (a15) (a16) (a17) (a18) (a19) and Robert A. Hegele (a1) (a2)...

Abstract:

Background/Objective:

Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.

Methods:

Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.

Results:

Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.

Conclusion:

This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.

Étude de variance génétique dans le cadre de l'initiative de recherche sur les maladies neurodégénératives en Ontario. Contexte/Objectif : L’apolipoprotéine E4 (ApoE4) constitue le principal facteur de risque génétique de la maladie d’Alzheimer. En raison de cette association systématique, il existe un intérêt certain à savoir dans quelle mesure cette classe d’apolipoprotéines peut influencer le risque d’autres maladies neurodégénératives. En outre, le milieu de la recherche n’a de cesse d’identifier d’autres biomarqueurs génétiques, par exemple les haplotypes H1 de la protéine tau associée aux microtubules, qui contribuent à certains phénotypes, Dans le cadre de cette étude, des participants à l'initiative de recherche sur les maladies neurodégénératives en Ontario ont été « génotypés » afin de déterminer si l’ApoE4 ou l’haplotype H1 mentionné ci-dessus peuvent être associés à cinq maladies neurodégénératives : 1) la maladie d’Alzheimer et d’autres troubles cognitifs légers ; 2) la sclérose latérale amyotrophique ; 3) la démence fronto-temporale ; 4) la maladie de Parkinson ; 5) et finalement les déficits cognitifs d’origine vasculaire. Méthodes : Pour chaque participant, la cartographie des génotypes a été établie en fonction de leur ApoE4 respectif et de la présence d’haplotypes H1 de la protéine tau associée aux microtubules. Des analyses de régression logistique ont été ensuite effectuées dans le but d’identifier de possibles liens avec ces maladies neurodégénératives. Résultats : Nos travaux ont confirmé l’association entre l’ApoE4 et une plus grande occurrence de cas d’Alzheimer, et ce, en tenant compte de l’effet d’une dose de médicament. Ils ont aussi montré une association entre la seule ApoE4 et des troubles cognitifs légers. Cela dit, il convient de préciser que les quatre autres maladies n’ont pas été associées à cet allèle. Plus encore, nous avons trouvé que l’allèle E2 de l’apolipoprotéine était associé à une occurrence plus faible de cas d’Alzheimer et de troubles cognitifs légers. Fait à souligner, aucune association n’a été détectée entre l’haplotype H1 de la protéine tau associée aux microtubules et nos cohortes atteintes de maladies neurodégénératives. Toutefois, à la suite du sous-typage de la cohorte de participants atteints de démence fronto-temporale, il s’est avéré que l’haplotype H1 était associé de façon notable à la paralysie supra-nucléaire progressive. Conclusion : Il s’agit de la première étude à analyser simultanément, au moyen de critères de participation cohérents et d’une analyse phénotypique élargie, les associations entre les isoformes de l’ApoE, l’haplotype H1 de la protéine tau associée aux microtubules et cinq maladies neurodégénératives.

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Copyright

Corresponding author

Correspondence to: Robert A. Hegele, Robarts Research Institute, Western University, 4288A-1151 Richmond Street North, London, ON, Canada, N6A 5C1, Email: hegele@robarts.ca

References

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1. Nalls, MA, Pankratz, N, Lill, CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet. 2014;46(9):989–93.
2. Lambert, JC, Ibrahim-Verbaas, CA, Harold, D, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452–8.
3. Simon-Sanchez, J, Schulte, C, Bras, JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet. 2009;41(12):1308–12.10.1038/ng.487
4. Bertram, L, McQueen, MB, Mullin, K, Blacker, D, Tanzi, RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39(1):1723.
5. Mahley, RW, Rall, SC , Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507–37.10.1146/annurev.genom.1.1.507
6. Kane, JW, Gowland, E. A method for the identification of apolipoprotein E isoforms employing chemical precipitation and flat bed isoelectric focusing in agarose. Ann Clin Biochem. 1986;23(Pt 5):509–13.
7. Zannis, VI, Breslow, JL, Utermann, G, et al. Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res. 1982;23(6):911–4.
8. Ward, A, Crean, S, Mercaldi, CJ, et al. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer’s disease: a systematic review and meta-analysis. Neuroepidemiology. 2012;38(1):117.10.1159/000334607
9. Corder, EH, Saunders, AM, Strittmatter, WJ, et al. 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.
10. Saunders, AM, Strittmatter, WJ, Schmechel, D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology. 1993;43(8):1467–72.
11. Liu, Y, Yu, JT, Wang, HF, et al. APOE genotype and neuroimaging markers of Alzheimer’s disease: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2015;86(2):127–34.10.1136/jnnp-2014-307719
12. Farrer, LA, Cupples, LA, Haines, JL, 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. JAMA. 1997;278(16):1349–56.
13. Mui, S, Rebeck, GW, McKenna-Yasek, D, Hyman, BT, Brown, RH , Jr. Apolipoprotein E epsilon 4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis. Ann Neurol. 1995;38(3):460–3.
14. Li, YJ, Pericak-Vance, MA, Haines, JL, et al. Apolipoprotein E is associated with age at onset of amyotrophic lateral sclerosis. Neurogenetics. 2004;5(4):209–13.
15. Agosta, F, Vossel, KA, Miller, BL, et al. Apolipoprotein E epsilon4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc Natl Acad Sci USA. 2009;106(6):2018–22.10.1073/pnas.0812697106
16. Geschwind, D, Karrim, J, Nelson, SF, Miller, B. The apolipoprotein E epsilon4 allele is not a significant risk factor for frontotemporal dementia. Ann Neurol. 1998;44(1):134–8.10.1002/ana.410440122
17. Ezquerra, M, Campdelacreu, J, Gaig, C, et al. Lack of association of APOE and tau polymorphisms with dementia in Parkinson’s disease. Neurosci Lett. 2008;448(1):20–3.
18. Pankratz, N, Byder, L, Halter, C, et al. Presence of an APOE4 allele results in significantly earlier onset of Parkinson’s disease and a higher risk with dementia. Mov Disord. 2006;21(1):45–9.
19. Huang, X, Chen, PC, Poole, C. APOE-[epsilon]2 allele associated with higher prevalence of sporadic Parkinson disease. Neurology. 2004;62(12):2198–202.
20. Baum, L, Lam, LC, Kwok, T, et al. Apolipoprotein E epsilon4 allele is associated with vascular dementia. Dement Geriatr Cogn Disord. 2006;22(4):301–5.
21. Davidson, Y, Gibbons, L, Purandare, N, et al. Apolipoprotein E epsilon4 allele frequency in vascular dementia. Dement Geriatr Cogn Disord. 2006;22(1):15–9.
22. Chuang, YF, Hayden, KM, Norton, MC, et al. Association between APOE epsilon4 allele and vascular dementia: The Cache County study. Dement Geriatr Cogn Disord. 2010;29(3):248–53.
23. Myers, AJ, Kaleem, M, Marlowe, L, et al. The H1c haplotype at the MAPT locus is associated with Alzheimer’s disease. Hum Mol Genet. 2005;14(16):2399–404.
24. Seto-Salvia, N, Clarimon, J, Pagonabarraga, J, et al. Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes. Arch Neurol. 2011;68(3):359–64.
25. Ferrari, R, Wang, Y, Vandrovcova, J, et al. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer’s and Parkinson’s diseases. J Neurol Neurosurg Psychiatry. 2017;88(2):152–64.
26. Baker, M, Litvan, I, Houlden, H, et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet. 1999;8(4):711–5.
27. Farhan, SM, Bartha, R, Black, SE, et al. The Ontario Neurodegenerative Disease Research Initiative (ONDRI). Can J Neurol Sci. 2017;44(2):196202.10.1017/cjn.2016.415
28. Farhan, SMK, Dilliott, AA, Ghani, G, et al. The ONDRISeq panel: custom-designed next-generation sequencing of genes related to neurodegeneration. NPJ Genom Med. 2016(16032):111.
29. Li, H, Wetten, S, Li, L, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008;65(1):4553.
30. Dilliott, AA, Farhan, SMK, Ghani, M, et al. Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease. J Vis Exp. 2018(134).
31. Wang, K, Li, M, Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.
32. Koch, W, Ehrenhaft, A, Griesser, K, et al. TaqMan systems for genotyping of disease-related polymorphisms present in the gene encoding apolipoprotein E. Clin Chem Lab Med. 2002;40(11):1123–31.
33. Lai, MC, Bechy, AL, Denk, F, et al. Haplotype-specific MAPT exon 3 expression regulated by common intronic polymorphisms associated with Parkinsonian disorders. Mol Neurodegener. 2017;12(1):79.10.1186/s13024-017-0224-6
34. Heffernan, AL, Chidgey, C, Peng, P, Masters, CL, Roberts, BR. The Neurobiology and Age-Related Prevalence of the epsilon4 Allele of Apolipoprotein E in Alzheimer’s Disease Cohorts. J Mol Neurosci. 2016;60(3):316–24.10.1007/s12031-016-0804-x
35. Elcoroaristizabal Martin, X, Fernandez Martinez, M, Galdos Alcelay, L, et al. Progression from amnesic mild cognitive impairment to Alzheimer’s disease: ESR1 and ESR2 polymorphisms and APOE gene. Dement Geriatr Cogn Disord. 2011;32(5):332–41.
36. Petersen, RC, Thomas, RG, Grundman, M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352(23):2379–88.
37. Fleisher, AS, Sowell, BB, Taylor, C, Gamst, AC, Petersen, RC, Thal, LJ. Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology. 2007;68(19):1588–95.
38. Corder, EH, Saunders, AM, Risch, NJ, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7(2):180–4.
39. Zhong, N, Weisgraber, KH. Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure. J Biol Chem. 2009;284(10):6027–31.
40. Yang, DS, Smith, JD, Zhou, Z, Gandy, SE, Martins, RN. Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma. J Neurochem. 1997;68(2):721–5.
41. Dumanis, SB, Tesoriero, JA, Babus, LW, et al. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J Neurosci. 2009;29(48):15317–22.
42. Miyata, M, Smith, JD. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet. 1996;14(1):5561.
43. Verghese, PB, Castellano, JM, Holtzman, DM. Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol. 2011;10(3):241–52.
44. Robinson, JL, Lee, EB, Xie, SX, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018;141(7):2181–93.

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Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative

  • Allison A. Dilliott (a1) (a2), Emily C. Evans (a3), Sali M.K. Farhan (a4), Mahdi Ghani (a5), Christine Sato (a5), Ming Zhang (a5), Adam D. McIntyre (a1), Henian Cao (a1), Lemuel Racacho (a6) (a7), John F. Robinson (a1), Michael J. Strong (a1) (a8), Mario Masellis (a9) (a10), Dennis E. Bulman (a6) (a7), Ekaterina Rogaeva (a5), Sandra E. Black (a9) (a11), Elizabeth Finger (a8) (a12), Andrew Frank (a13), Morris Freedman (a10) (a14) (a15), Ayman Hassan (a16), Anthony Lang (a10) (a17), Christen L. Shoesmith (a8), Richard H. Swartz (a9), David Tang-Wai (a10) (a18), Maria Carmela Tartaglia (a5) (a10), John Turnbull (a19), Lorne Zinman (a9), the ONDRI Investigators (a1) (a2) (a3) (a4) (a5) (a6) (a7) (a8) (a9) (a10) (a11) (a12) (a13) (a14) (a15) (a16) (a17) (a18) (a19) and Robert A. Hegele (a1) (a2)...

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