title: Linkage and association study of late-onset Alzheimer disease families linked to 9p21.3.
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.
authors.affiliation: Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. szuchner@med.miami.edu
authors.forename: S
authors.initials: S
authors.lastname: Züchner
authors.forename: J R
authors.initials: JR
authors.lastname: Gilbert
authors.forename: E R
authors.initials: ER
authors.lastname: Martin
authors.forename: C R
authors.initials: CR
authors.lastname: Leon-Guerrero
authors.forename: P-T
authors.initials: PT
authors.lastname: Xu
authors.forename: C
authors.initials: C
authors.lastname: Browning
authors.forename: P G
authors.initials: PG
authors.lastname: Bronson
authors.forename: P
authors.initials: P
authors.lastname: Whitehead
authors.forename: D E
authors.initials: DE
authors.lastname: Schmechel
authors.forename: J L
authors.initials: JL
authors.lastname: Haines
authors.forename: M A
authors.initials: MA
authors.lastname: Pericak-Vance