Linkage and association study of late-onset Alzheimer disease families linked to 9p21.3.
Annals of Human Genetics
Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Chromosomes, Human, Pair 9; Family; Genes, p16; Genetic Linkage; Genetic Predisposition to Disease; Humans; Middle Aged; Polymorphism, Single Nucleotide
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.
Züchner, S., Gilbert, J., Martin, E., Leon-Guerrero, C., Xu, P., Browning, C., Bronson, P., Whitehead, P., Schmechel, D., Haines, J., & Pericak-Vance, M. (2008). Linkage and association study of late-onset Alzheimer disease families linked to 9p21.3.. Annals of Human Genetics, 72 (Pt 6). http://dx.doi.org/10.1111/j.1469-1809.2008.00474.x