A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease

Abstract

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates 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 they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

Figure A1

Count of markers used in the exploratory samples by SNP types. Note that the categorization of the unknown (intergenic) and silent mutation SNPs is based on the most current genome assembly (Celera Genome Assembly R27). In previous genome assemblies, these SNPs belonged to functional categories as well.

Figure 1

Allelic P values of 1,397 exploratory markers from the exploratory sample (middle), with a bar graph showing the distribution of annotated genes across chromosome 10 (bottom). Marker rs498055 is noted with an arrow, and a P value of .05 is marked with a line. The previously identified linkage peak regions are noted with solid lines and references (top). Studies with multipoint LOD scores >2 in white samples were included. Results of single-marker studies were not included.

Figure 2

Allelic P values of markers around the RPS3A homologue region (LOC43999) in both exploratory and validation samples, along with a gene map of the region and Celera assembly coordinates (in Mbp). Blue diamonds indicate two-sided explatory sample P values; the other symbols indicate one-sided replication sample P values for WU (red squares), UCSD (gray triangles), and UK (green circle).

Figure 3

Haplotype networks. Each oval contains the haplotype identification number, the state at each locus, and the number of times it was inferred to occur in this sample set. To simplify the presentation of the network, haplotypes that appear only once in the sample are not shown, and selected haplotypes have been collapsed. The branch that was significant in the tree scan is denoted by the dashed line. P values for the original and conditional analyses are also provided. Mutations at rs498055 are indicated by “T⟷C”; the mutation at rs495998 is indicated by “A⟷C.”