P1-362: Genetic Evaluation of the Alzheimer’s Disease Locus on Chromosome 9P21.3

In a genome wide microsatellite–based linkage screen on Alzheimer's disease (AD) families of European descent we previously mapped a new chromosomal locus to 9p21.3. The peak LOD score occurred at D9S171 (24.5 Mbp) in a subset of 199 families with at least one autopsy–confirmed AD case. This linkage was independently confirmed by Farrer et al. in AD families from a consanguineous Israeli–Arab community. In an updated sample of 311 autopsy–confirmed AD families, we genotyped 98 SNPs across a chromosomal region of 19 Mbp (18.6–37.8 Mbp). Additionally, we re–sequenced the coding area of a number of AD candidate genes in this chromosomal area in 48 autopsy confirmed AD cases. Marker D9S171 yielded a single–point heterogeneity LOD score of 3.48 under the recessive disease model. Linkage analysis of SNPs generated a peak single–point heterogeneity LOD score of 2.67 at rs1034168, (24.6 Mbp). The next highest LOD score was 2.41 at rs3731249 (21.96 Mbp), which is in the cyclin–dependent kinase inhibitor 2A (CDKN2A) gene. Also in CDKN2A is rs11515, which yielded the most significant allelic (p=0.003) association. Although we identified novel sequence variants by re–sequencing no significant association was detected with AD. Changes in expression of CDKN2A have repeatedly been reported in AD brains and a number of cyclin–dependent kinases are elevated in neurons prone to dedifferentiation and degeneration. So far, the CDKN2A gene appears to be a promising new candidate gene potentially contributing to AD susceptibility on chromosome 9p.