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

Stephen Züchner, J. R. Gilbert, E. R. Martin, C. R. Leon-Guerrero, P. T. Xu, C. Browning, P. G. Bronson, P. Whitehead, D. E. Schmechel, J. L. Haines, M. A. Pericak-Vance

Research output: Contribution to journalArticle

28 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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    Züchner, S., Gilbert, J. R., Martin, E. R., Leon-Guerrero, C. R., Xu, P. T., Browning, C., Bronson, P. G., Whitehead, P., Schmechel, D. E., Haines, J. L., & Pericak-Vance, M. A. (2008). Linkage and association study of late-onset alzheimer disease families linked to 9p21.3. Annals of Human Genetics, 72(6), 725-731. https://doi.org/10.1111/j.1469-1809.2008.00474.x