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

Andrew Grupe, Yonghong Li, Charles Rowland, Petra Nowotny, Anthony L. Hinrichs, Scott Smemo, John S.K. Kauwe, Taylor J. Maxwell, Sara Cherny, Lisa Doil, Kristina Tacey, Ryan Van Luchene, Amanda Myers, Fabienne Wavrant-De Vrièze, Mona Kaleem, Paul Hollingworth, Luke Jehu, Catherine Foy, Nicola Archer, Gillian HamiltonPeter Holmans, Chris M. Morris, Joseph Catanese, John Sninsky, Thomas J. White, John Powell, John Hardy, Michael O'Donovan, Simon Lovestone, Lesley Jones, John C. Morris, Leon Thal, Michael Owen, Julie Williams, Alison Goate

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113 Scopus citations

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.

Original languageEnglish
Pages (from-to)78-88
Number of pages11
JournalAmerican journal of human genetics
Volume78
Issue number1
DOIs
StatePublished - Jan 2006

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    Grupe, A., Li, Y., Rowland, C., Nowotny, P., Hinrichs, A. L., Smemo, S., Kauwe, J. S. K., Maxwell, T. J., Cherny, S., Doil, L., Tacey, K., Van Luchene, R., Myers, A., Wavrant-De Vrièze, F., Kaleem, M., Hollingworth, P., Jehu, L., Foy, C., Archer, N., ... Goate, A. (2006). A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. American journal of human genetics, 78(1), 78-88. https://doi.org/10.1086/498851