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Neurogenetics

, Volume 7, Issue 3, pp 157–165 | Cite as

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

  • Ping-I Lin
  • Eden R. Martin
  • Carrie A. Browning-Large
  • Donald E. Schmechel
  • Kathleen A. Welsh-Bohmer
  • P. Murali Doraiswamy
  • John R. Gilbert
  • Jonathan L. Haines
  • Margaret A. Pericak-Vance
Original Article

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.

Keywords

Alzheimer disease APOE Association study SNPs Haplotype 

Notes

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.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Ping-I Lin
    • 1
  • Eden R. Martin
    • 1
  • Carrie A. Browning-Large
    • 1
  • Donald E. Schmechel
    • 1
  • Kathleen A. Welsh-Bohmer
    • 2
  • P. Murali Doraiswamy
    • 2
  • John R. Gilbert
    • 1
  • Jonathan L. Haines
    • 3
  • Margaret A. Pericak-Vance
    • 1
  1. 1.Center for Human GeneticsDuke University Medical CenterDurhamUSA
  2. 2.Department of Psychiatry and Behavioral SciencesDuke University Medical CenterDurhamUSA
  3. 3.Center for Human Genetics ResearchVanderbilt UniversityNashvilleUSA

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