Skip to main content

Advertisement

SpringerLink
Log in

Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis

  • Original Article
  • Published:
Neurogenetics Aims and scope Submit manuscript

Abstract

Previous linkage studies have suggested that chromosome 12 may harbor susceptibility genes for late-onset Alzheimer disease (LOAD). No risk genes on chromosome 12 have been conclusively identified yet. We have reported that the linkage evidence for LOAD in a 12q region was significantly increased in autopsy-confirmed families particularly for those showing no linkage to alpha-T catenin gene, a LOAD candidate gene on chromosome 10 [LOD score increased from 0.1 in the autopsy-confirmed subset to 4.19 in the unlinked subset (optimal subset); p<0.0001 for the increase in LOD score], indicating a one-LOD support interval spanning 6 Mb. To further investigate this finding and to identify potential candidate LOAD risk genes for follow-up analysis, we analyzed 99 single nucleotide polymorphisms in this region, for the overall sample, the autopsy-confirmed subset, and the optimal subset, respectively, for comparison. We saw no significant association (p<0.01) in the overall sample. In the autopsy-confirmed subset, the best finding was obtained in the activation transcription factor 7 (ATF7) gene (single-locus association, p=0.002; haplotype association global, p=0.007). In the optimal subset, the best finding was obtained in the hypothetical protein FLJ20436 (FLJ20436) gene (single-locus association, p=0.0026). These results suggest that subset and covariate analyses may be one approach to help identify novel susceptibility genes on chromosome 12q for LOAD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Farrer LA, Cupples LA, Haines J, Hyman B, Kukull W, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, gender, and ethnicity on the association between APOE genotype and Alzheimer disease. JAMA 278:1349–1356

    Article  PubMed  CAS  Google Scholar 

  2. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  PubMed  CAS  Google Scholar 

  3. Pericak-Vance MA, Bass MP, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA, Menold MM, Conneally PM, Small GW, Vance JM, Saunders AM, Roses AD, Haines JL (1997) Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA 278:1237–1241

    Article  PubMed  CAS  Google Scholar 

  4. Pericak-Vance MA, Bass ML, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA, Menold MM, Conneally PM, Small GW, Saunders AM, Roses AD, Haines JL (1998) Complete genomic screen in late-onset familial Alzheimer’s disease. Neurobiol Aging 19:S39–S42

    Article  PubMed  CAS  Google Scholar 

  5. Rogaeva E, Premkumar S, Song Y, Sorbi S, Brindle N, Paterson A, Duara R, Levesque G, Yu G, Nishimura M, Ikeda M, O’Toole C, Kawarai T, Jorge R, Vilarino D, Bruni AC, Farrer LA, St George-Hyslop PH (1998) Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. JAMA 280:614–618

    Article  PubMed  CAS  Google Scholar 

  6. Scott WK, Grubber JM, Abou-donia SM, Church TD, Yamaoka LH, Conneally PM, dSmall GW, Saunders AM, Roses AD, Haines JL, Pericak-Vance MA (1998) Fine mapping and two-locus maximum lod score analysis in chromosome 12-linked late-onset familial Alzheimer disease (AD). Am J Hum Genet 63:A44

    Google Scholar 

  7. Scott WK, Grubber JM, Conneally PM, Small GW, Hulette CM, Rosenberg CK, Saunders AM, Roses AD, Haines JL, Pericak-Vance MA (2000) Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet 66:922–932

    Article  PubMed  CAS  Google Scholar 

  8. Mayeux R, Lee JH, Romas SN, Mayo D, Santana V, Williamson J, Ciappa A, Rondon HZ, Estevez P, Lantigua R, Medrano M, Torres M, Stern Y, Tycko B, Knowles JA (2002) Chromosome-12 mapping of late-onset Alzheimer disease among Caribbean Hispanics. Am J Hum Genet 70:237–243

    Article  PubMed  CAS  Google Scholar 

  9. Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, Selkoe DJ, Saunders AJ, Tanzi RE (2000) Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science 290:2302–2303

    Article  PubMed  CAS  Google Scholar 

  10. Myers A, Holmans P, Marshall H, Kwon J, Meyer D, Ramic D, Shears S, Booth J, DeVrieze FW, Crook R, Hamshere M, Abraham R, Tunstall N, Rice F, Carty S, Lillystone S, Kehoe P, Rudrasingham V, Jones L, Lovestone S, Perez-Tur J, Williams J, Owen MJ, Hardy J, Goate AM (2000) Susceptibility locus for Alzheimer’s disease on chromosome 10. Science 290:2304–2305

    Article  PubMed  CAS  Google Scholar 

  11. Ertekin-Taner N, Graff-Radford N, Younkin LH, Eckman C, Baker M, Adamson J, Ronald J, Blangero J, Hutton M, Younkin SG (2000) Linkage of plasma Aβ42 to a quantitative locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Science 290:2303–2304

    Article  PubMed  CAS  Google Scholar 

  12. Ertekin-Taner N, Ronald J, Asahara H, Younkin L, Hella M, Jain S, Gnida E, Younkin S, Fadale D, Ohyagi Y, Singleton A, Scanlin L, De Andrade M, Petersen R, Graff-Radford N, Hutton M, Younkin S (2003) Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Hum Mol Genet 12:3133–3143

    Article  PubMed  CAS  Google Scholar 

  13. Liang X, Schnetz-Boutaud N, Kenealy SJ, Jiang L, Bartlett J, Lynch B, Gaskell PC, Gwirtsman H, McFarland L, Bembe ML, Bronson P, Gilbert JR, Martin ER, Pericak-Vance MA, Haines JL (2005) Covariate analysis of late-onset Alzheimer disease refines the chromosome 12 locus. Mol Psychiatry 11(3):280–285

    Article  Google Scholar 

  14. Hauser ER, Watanabe RM, Duren WL, Bass MP, Langefeld CD, Boehnke M (2004) Ordered subset analysis in genetic linkage mapping of complex traits. Genet Epidemiol 27:53–63

    Article  PubMed  Google Scholar 

  15. Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF (1994) Reliability and validity of NINCDS-ADRDA criteria for Alzheimer’s disease. The National Institute of Mental Health Genetics Initiative. Arch Neurol 51:1198–1204

    PubMed  CAS  Google Scholar 

  16. McKhann G, Drachman D, Folstein M (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944

    PubMed  CAS  Google Scholar 

  17. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, Van Belle G, Berg L (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  18. Mirra SS, Hart MN, Terry RD (1993) Making the diagnosis of Alzheimer’s disease. A primer for practicing pathologists. Arch Pathol Lab Med 117:132–144

    PubMed  CAS  Google Scholar 

  19. Oliveira SA, Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons KE, Pahwa R, Stern MB, Hiner BC, Jankovic J, Ondo WG, Allen FH Jr, Scott BL, Goetz CG, Small GW, Mastaglia FL, Stajich JM, Zhang F, Booze MW, Reaves JA, Middleton LT, Haines JL, Pericak-Vance MA, Vance JM, Martin ER (2003) Association study of Parkin gene polymorphisms with idiopathic Parkinson disease. Arch Neurol 60:975–980

    Article  PubMed  Google Scholar 

  20. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472

    PubMed  CAS  Google Scholar 

  21. Liang K, Zeger SL (1986) Longitudinal data analysis using generalized linear models. Biometrika 73:13–22

    Article  Google Scholar 

  22. Lewis PO, Zaykin D (2000) Genetic data analysis: computer program for analysis of allelic data, version 1.0 (d15)

  23. Abecasis GR, Cookson WO (2000) GOLD—graphical overview of linkage disequilibrium. Bioinformatics 16:182–183

    Article  PubMed  CAS  Google Scholar 

  24. Martin ER, Bass MP, Hauser ER, Kaplan NL (2003) Accounting for linkage in family-based tests of association with missing parental genotypes. Am J Hum Genet 73:1016–1026

    Article  PubMed  CAS  Google Scholar 

  25. Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM (2004) Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 26:61–69

    Article  PubMed  Google Scholar 

  26. Long AD, Langley CH (1999) The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Res 9:720–731

    PubMed  CAS  Google Scholar 

  27. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc 57:289–300

    Google Scholar 

  28. Li Y, Nowotny P, Holmans P, Smemo S, Kauwe JS, Hinrichs AL, Tacey K, Doil L, van Luchene R, Garcia V, Rowland C, Schrodi S, Leong D, Gogic G, Chan J, Cravchik A, Ross D, Lau K, Kwok S, Chang SY, Catanese J, Sninsky J, White TJ, Hardy J, Powell J, Lovestone S, Morris JC, Thal L, Owen M, Williams J, Goate A, Grupe A (2004) Association of late-onset Alzheimer’s disease with genetic variation in multiple members of the GAPD gene family. Proc Natl Acad Sci USA

Download references

Acknowledgements

We thank the patients with Alzheimer disease and their families whose help and participation made this work possible. We also thank the personnel of the Duke CHG, Vanderbilt CHGR, and the Joseph and Kathleen Bryan ADRC. Furthermore, we thank Dr. Donald E. Schmechel for his help on our AD ascertainment and Dr. Christine Hulette for her effort in obtaining neuropathological information on the Duke subset of families. This work was supported by the National Institute of Health (NIH) AG021547 (MPV), AG19757 (MPV), AG05128 (MPV), AG20135 (ERM) grants and NS311530 (Jeffery M Vance); a T.L.L. Temple Award (TLL-97-012); and a Zenith Award (ZEN-01-2935) from the Alzheimer’s Association (MPV). We appreciate the biomaterial and clinical data contributed by Indiana Alzheimer’s Disease Research Center National Cell Repository (IADRC). The NIMH data and biomaterials were collected in three projects that participated in the NIMH Alzheimer Disease Genetics Initiative. From 1991–1998, the principal investigators and co-investigators were: Massachusetts General Hospital, Boston, MA, U01 MH46281, Marilyn S. Albert, Ph.D., and Deborah Blacker, M.D., Sc.D.; Johns Hopkins University, Baltimore, MD, U01 MH46290, Susan S. Bassett, Ph.D., Gary A. Chase, Ph.D., and Marshal F. Folstein, M.D.; University of Alabama, Birmingham, AL, U01 MH46373, Rodney C.P. Go, Ph.D., and Lindy E. Harrell, M.D.

Author information

Authors and Affiliations

  1. Center for Human Genetics, Duke University Medical Center, Durham, NC, USA

    Ping-I Lin, Eden R. Martin, Carrie A. Browning-Large, Donald E. Schmechel, John R. Gilbert & Margaret A. Pericak-Vance

  2. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

    Kathleen A. Welsh-Bohmer & P. Murali Doraiswamy

  3. Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

    Jonathan L. Haines

Authors
  1. Ping-I Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eden R. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carrie A. Browning-Large
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Donald E. Schmechel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathleen A. Welsh-Bohmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. Murali Doraiswamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John R. Gilbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jonathan L. Haines
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Margaret A. Pericak-Vance
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Margaret A. Pericak-Vance.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, PI., Martin, E.R., Browning-Large, C.A. et al. Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis. Neurogenetics 7, 157–165 (2006). https://doi.org/10.1007/s10048-006-0047-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-006-0047-z

Keywords

Search

Navigation