Linkage and Association Study of Late‐Onset Alzheimer Disease Families Linked to 9p21.3

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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.