neurogenetics

, Volume 10, Issue 1, pp 19–25

Assessment of Alzheimer’s disease case–control associations using family-based methods

  • Brit-Maren M. Schjeide
  • Matthew B. McQueen
  • Kristina Mullin
  • Jason DiVito
  • Meghan F. Hogan
  • Michele Parkinson
  • Basavaraj Hooli
  • Christoph Lange
  • Deborah Blacker
  • Rudolph E. Tanzi
  • Lars Bertram
Original Article

Abstract

The genetics of Alzheimer’s disease (AD) is heterogeneous and remains only ill-defined. We have recently created a freely available and continuously updated online database (AlzGene; http://www.alzgene.org) for which we collect all published genetic association studies in AD and perform systematic meta-analyses on all polymorphisms with sufficient genotype data. In this study, we tested 27 genes (ACE, BDNF, CH25H, CHRNB2, CST3, CTSD, DAPK1, GALP, hCG2039140, IL1B, LMNA, LOC439999, LOC651924, MAPT, MTHFR, MYH13, PCK1, PGBD1, PRNP, PSEN1, SORCS1, SORL1, TF, TFAM, TNK1, GWA_14q32.13, and GWA_7p15.2), all showing significant association with AD risk in the AlzGene meta-analyses, in a large collection of family-based samples comprised of 4,180 subjects from over 1,300 pedigrees. Overall, we observe significant association with risk for AD and polymorphisms in ACE, CHRNB2, TF, and an as yet uncharacterized locus on chromosome 7p15.2 [rs1859849]. For all four loci, the association was observed with the same alleles as in the AlzGene meta-analyses. The convergence of case–control and family-based findings suggests that these loci currently represent the most promising AD gene candidates. Further fine-mapping and functional analyses are warranted to elucidate the potential biochemical mechanisms and epidemiological relevance of these genes.

Keywords

Alzheimer’s disease Risk factors Genetic association Meta-analysis Family-based association testing 

Supplementary material

10048_2008_151_MOESM1_ESM.doc (908 kb)
ESM 1(DOC 908 KB)

References

  1. 1.
    Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39:17–23. doi:10.1038/ng1934 CrossRefPubMedGoogle Scholar
  2. 2.
    Bertram L, Blacker D, Crystal A, Mullin K, Keeney D, Jones J et al (2000) Candidate genes showing no evidence for association or linkage with Alzheimer’s disease using family-based methodologies. Exp Gerontol 35:1353–1361. doi:10.1016/S0531-5565(00)00193-5 CrossRefPubMedGoogle Scholar
  3. 3.
    Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F et al (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177. doi:10.1038/ng1943 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Laird NM, Lange C (2006) Family-based designs in the age of large-scale gene-association studies. Nat Rev Genet 7:385–394. doi:10.1038/nrg1839 CrossRefPubMedGoogle Scholar
  5. 5.
    Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE et al (1997) ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative. Neurology 48:139–147CrossRefPubMedGoogle Scholar
  6. 6.
    Bertram L, Hiltunen M, Parkinson M, Ingelsson M, Lange C, Ramasamy K et al (2005) Family-based association between Alzheimer’s disease and variants in UBQLN1. N Engl J Med 352:884–894. doi:10.1056/NEJMoa042765 CrossRefPubMedGoogle Scholar
  7. 7.
    Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC (2006) ACE polymorphisms. Circ Res 98:1123–1133. doi:10.1161/01.RES.0000223145.74217.e7 CrossRefPubMedGoogle Scholar
  8. 8.
    Rabinowitz D, Laird N (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 50:211–223. doi:10.1159/000022918 CrossRefPubMedGoogle Scholar
  9. 9.
    Fisher RA (1932) Statistical methods for research workers. Oliver and Boyd, EdinburghGoogle Scholar
  10. 10.
    Witte JS, Gauderman WJ, Thomas DC (1999) Asymptotic bias and efficiency in case-control studies of candidate genes and gene-environment interactions: basic family designs. Am J Epidemiol 149:693–705CrossRefPubMedGoogle Scholar
  11. 11.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188. doi:10.1016/0197-2456(86)90046-2 CrossRefPubMedGoogle Scholar
  12. 12.
    Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM (2004) PBAT: tools for family-based association studies. Am J Hum Genet 74:367–369. doi:10.1086/381563 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A et al (2007) Evidence for novel susceptibility genes for late-onset Alzheimer’s disease from a genome-wide association study of putative functional variants. Hum Mol Genet 16:865–873. doi:10.1093/hmg/ddm031 CrossRefPubMedGoogle Scholar
  14. 14.
    Kauwe JS, Wang J, Mayo K, Morris JC, Fagan AM, Holtzman DM, Goate AM (2009) Alzheimer’s disease risk variants show association with cerebrospinal fluid amyloid beta. Neurogenetics. doi:10.1007/s10048-008-0150-4
  15. 15.
    Takeda S, Sato N, Ogihara T, Morishita R (2008) The renin-angiotensin system, hypertension and cognitive dysfunction in Alzheimer’s disease: new therapeutic potential. Front Biosci 13:2253–2265. doi:10.2741/2839 CrossRefPubMedGoogle Scholar
  16. 16.
    Keavney B, McKenzie CA, Connell JM, Julier C, Ratcliffe PJ, Sobel E et al (1998) Measured haplotype analysis of the angiotensin-I converting enzyme gene. Hum Mol Genet 7:1745–1751. doi:10.1093/hmg/7.11.1745 CrossRefPubMedGoogle Scholar
  17. 17.
    Kehoe PG, Katzov H, Feuk L, Bennet AM, Johansson B, Wiman B et al (2003) Haplotypes extending across ACE are associated with Alzheimer’s disease. Hum Mol Genet 12:859–867. doi:10.1093/hmg/ddg094 CrossRefPubMedGoogle Scholar
  18. 18.
    Miners JS, Ashby E, Van Helmond Z, Chalmers KA, Palmer LE, Love S et al (2008) Angiotensin-converting enzyme (ACE) levels and activity in Alzheimer’s disease, and relationship of perivascular ACE-1 to cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 34:181–193. doi:10.1111/j.1365–2990.2007.00885.x CrossRefPubMedGoogle Scholar
  19. 19.
    Hu J, Igarashi A, Kamata M, Nakagawa H (2001) Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem 276:47863–47868PubMedGoogle Scholar
  20. 20.
    Eckman EA, Adams SK, Troendle FJ, Stodola BA, Kahn MA, Fauq AH et al (2006) Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme. J Biol Chem 281:30471–30478. doi:10.1074/jbc.M605827200 CrossRefPubMedGoogle Scholar
  21. 21.
    Hemming ML, Selkoe DJ, Farris W (2007) Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease. Neurobiol Dis 26:273–281CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Brewer GJ (2007) Iron and copper toxicity in diseases of aging, particularly atherosclerosis and Alzheimer’s disease. Exp Biol Med (Maywood) 232:323–335Google Scholar
  23. 23.
    Loeffler DA, Connor JR, Juneau PL, Snyder BS, Kanaley L, DeMaggio AJ et al (1995) Transferrin and iron in normal, Alzheimer’s disease, and Parkinson’s disease brain regions. J Neurochem 65:710–724CrossRefPubMedGoogle Scholar
  24. 24.
    Smith MA, Harris PL, Sayre LM, Perry G (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A 94:9866–9868. doi:10.1073/pnas.94.18.9866 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yamamoto A, Shin RW, Hasegawa K, Naiki H, Sato H, Yoshimasu F et al (2002) Iron (III) induces aggregation of hyperphosphorylated tau and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer’s disease. J Neurochem 82:1137–1147CrossRefPubMedGoogle Scholar
  26. 26.
    Lee PL, Ho NJ, Olson R, Beutler E (1999) The effect of transferrin polymorphisms on iron metabolism. Blood Cells Mol Dis 25:374–379. doi:10.1006/bcmd.1999.0267 CrossRefPubMedGoogle Scholar
  27. 27.
    Zatta P, Messori L, Mauri P, van Rensburg SJ, van Zyl J, Gabrielli S et al (2005) The C2 variant of human serum transferrin retains the iron binding properties of the native protein. Biochim Biophys Acta 1741:264–270CrossRefPubMedGoogle Scholar
  28. 28.
    Kalamida D, Poulas K, Avramopoulou V, Fostieri E, Lagoumintzis G, Lazaridis K et al (2007) Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity. FEBS J 274:3799–3845. doi:10.1111/j.1742–4658.2007.05935.x CrossRefPubMedGoogle Scholar
  29. 29.
    Oddo S, LaFerla FM (2006) The role of nicotinic acetylcholine receptors in Alzheimer’s disease. J Physiol (Paris) 99:172–179. doi:10.1016/j.jphysparis.2005.12.080 CrossRefGoogle Scholar
  30. 30.
    Tohgi H, Utsugisawa K, Yoshimura M, Nagane Y, Mihara M (1998) Age-related changes in nicotinic acetylcholine receptor subunits alpha4 and beta2 messenger RNA expression in postmortem human frontal cortex and hippocampus. Neurosci Lett 245:139–142. doi:10.1016/S0304-3940(98)00205-5 CrossRefPubMedGoogle Scholar
  31. 31.
    Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al (1997) 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 278:1349–1356. doi:10.1001/jama.278.16.1349 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Brit-Maren M. Schjeide
    • 1
  • Matthew B. McQueen
    • 2
    • 3
  • Kristina Mullin
    • 1
  • Jason DiVito
    • 1
  • Meghan F. Hogan
    • 1
  • Michele Parkinson
    • 1
  • Basavaraj Hooli
    • 1
  • Christoph Lange
    • 4
  • Deborah Blacker
    • 2
    • 5
  • Rudolph E. Tanzi
    • 1
  • Lars Bertram
    • 1
  1. 1.Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease (MIND)Department of Neurology, Massachusetts General Hospital, MGH-East (MIND)CharlestownUSA
  2. 2.Department of EpidemiologyHarvard School of Public HealthBostonUSA
  3. 3.Institute for Behavioral GeneticsUniversity of ColoradoBoulderUSA
  4. 4.Department of BiostatisticsHarvard School of Public HealthBostonUSA
  5. 5.Gerontology Research Unit, Department of PsychiatryMassachusetts General HospitalCharlestownUSA

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