A Scan of Chromosome 10 Identifies Novel Candidate Genes Showing Strong Association to Late-Onset Alzheimer's Disease. J.S.K. Kauwe III¹, A. Grupe², Y. Li², C. Rowland², P. Nowotny¹, A.L. Hinrichs¹, S. Smemo¹, L. Doil², K. Tacey², P. Holmans³, J. Hardy⁵, M. O'Donovan³, S. Lovestone⁶, L. Jones³, J. Morris¹, L. Thal⁴, M. Owen³, J. Williams³, A. Goate¹. 1) Washington Univ Sch of Med, St Louis, MO; 2) Celera Diagnostics, Alameda, CA; 3) Cardiff Univ, Wales College of Med, Cardiff, UK; 4) Univ of California, San Diego, La Jolla, CA; 5) National Institute on Aging, Bethesda, MD; 6) King's College London, London, UK.

   Evidence of linkage to late-onset Alzheimers disease (LOAD) has been observed on chromosome 10, implicating a wide region and at least one disease susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated and remain controversial. We performed a chromosome 10 specific association study with 1,430 single nucleotide polymorphisms (SNPs, allele frequency 2%). The scan covered 728 genes with one or more markers per gene. Initial tests were performed in a Caucasian case-control sample from the St. Louis area with 419 LOAD cases and 377 aged-matched controls. Markers that showed significant association in the exploratory analysis were followed up in two other Caucasian case-control sample sets to confirm the initial association. The replication case-control sets included a total of 670 LOAD cases and 819 controls, collected in the San Diego area and in the UK. Of the 1,398 markers tested in the exploratory sample, 69 reached significance (P=<0.05). Of these, 5 markers were replicated at P<0.05. One marker, rs498055, located in a gene homologous to RPS3A, was significantly associated with AD in each of the three case-control series, with an allelic P-value of 0.00004 (OR=1.3) in the meta-analysis. This marker was also tested in a case-control sample derived from our linkage sample (P=0.0165 OR=1.257). These results indicate that variants in the RPS3A homolog and haplotypes in the RPS3A homolog region are associated with LOAD and implicate this gene, adjacent genes or other functional variants (e.g. non-coding RNAs) in the pathogenesis of this disorder.