Linkage and association study of late-onset alzheimer disease families linked to 9p21.3

Stephan L Zuchner, John Gilbert, Eden R Martin, C. R. Leon-Guerrero, P. T. Xu, C. Browning, P. G. Bronson, P. Whitehead, D. E. Schmechel, J. L. Haines, Margaret A Pericak-Vance

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

A chromosomal locus for late-onset Alzheimer disease (LOAD) has previously been mapped to 9p21.3. The most significant results were reported in a sample of autopsy-confirmed families. Linkage to this locus has been independently confirmed in AD families from a consanguineous Israeli-Arab community. In the present study we analyzed an expanded clinical sample of 674 late-onset AD families, independently ascertained by three different consortia. Sample subsets were stratified by site and autopsy-confirmation. Linkage analysis of a dense array of SNPs across the chromosomal locus revealed the most significant results in the 166 autopsy-confirmed families of the NIMH sample. Peak HLOD scores of 4.95 at D9S741 and 2.81 at the nearby SNP rs2772677 were obtained in a dominant model. The linked region included the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), which has been suggested as an AD candidate gene. By re-sequencing all exons in the vicinity of CDKN2A in 48 AD cases, we identified and genotyped four novel SNPs, including a non-synonymous, a synonymous, and two variations located in untranslated RNA sequences. Family-based allelic and genotypic association analysis yielded significant results in CDKN2A (rs11515: PDT p = 0.003, genotype-PDT p = 0.014). We conclude that CDKN2A is a promising new candidate gene potentially contributing to AD susceptibility on chromosome 9p.

Original languageEnglish
Pages (from-to)725-731
Number of pages7
JournalAnnals of Human Genetics
Volume72
Issue number6
DOIs
StatePublished - Oct 22 2008

Fingerprint

Cyclin-Dependent Kinase Inhibitor p16
Alzheimer Disease
Genes
Single Nucleotide Polymorphism
Autopsy
National Institute of Mental Health (U.S.)
Untranslated RNA
Exons
Chromosomes
Genotype
1-phenyl-3,3-dimethyltriazene

Keywords

  • Alzheimer disease
  • Associationstudy
  • Cyclin-dependent kinase inhibitor 2B
  • Linkage study

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Linkage and association study of late-onset alzheimer disease families linked to 9p21.3. / Zuchner, Stephan L; Gilbert, John; Martin, Eden R; Leon-Guerrero, C. R.; Xu, P. T.; Browning, C.; Bronson, P. G.; Whitehead, P.; Schmechel, D. E.; Haines, J. L.; Pericak-Vance, Margaret A.

In: Annals of Human Genetics, Vol. 72, No. 6, 22.10.2008, p. 725-731.

Research output: Contribution to journalArticle

Zuchner, SL, Gilbert, J, Martin, ER, Leon-Guerrero, CR, Xu, PT, Browning, C, Bronson, PG, Whitehead, P, Schmechel, DE, Haines, JL & Pericak-Vance, MA 2008, 'Linkage and association study of late-onset alzheimer disease families linked to 9p21.3', Annals of Human Genetics, vol. 72, no. 6, pp. 725-731. https://doi.org/10.1111/j.1469-1809.2008.00474.x
Zuchner, Stephan L ; Gilbert, John ; Martin, Eden R ; Leon-Guerrero, C. R. ; Xu, P. T. ; Browning, C. ; Bronson, P. G. ; Whitehead, P. ; Schmechel, D. E. ; Haines, J. L. ; Pericak-Vance, Margaret A. / Linkage and association study of late-onset alzheimer disease families linked to 9p21.3. In: Annals of Human Genetics. 2008 ; Vol. 72, No. 6. pp. 725-731.
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