title: 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.
authors.affiliation: Celera Diagnostics, Alameda, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Grupe
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Li
authors.forename: Charles
authors.initials: C
authors.lastname: Rowland
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Hinrichs
authors.forename: Scott
authors.initials: S
authors.lastname: Smemo
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Maxwell
authors.forename: Sara
authors.initials: S
authors.lastname: Cherny
authors.forename: Lisa
authors.initials: L
authors.lastname: Doil
authors.forename: Kristina
authors.initials: K
authors.lastname: Tacey
authors.forename: Ryan
authors.initials: R
authors.lastname: van Luchene
authors.forename: Amanda
authors.initials: A
authors.lastname: Myers
authors.forename: Fabienne
authors.initials: F
authors.lastname: Wavrant-De Vrièze
authors.forename: Mona
authors.initials: M
authors.lastname: Kaleem
authors.forename: Paul
authors.initials: P
authors.lastname: Hollingworth
authors.forename: Luke
authors.initials: L
authors.lastname: Jehu
authors.forename: Catherine
authors.initials: C
authors.lastname: Foy
authors.forename: Nicola
authors.initials: N
authors.lastname: Archer
authors.forename: Gillian
authors.initials: G
authors.lastname: Hamilton
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Chris M
authors.initials: CM
authors.lastname: Morris
authors.forename: Joseph
authors.initials: J
authors.lastname: Catanese
authors.forename: John
authors.initials: J
authors.lastname: Sninsky
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: White
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Lesley
authors.initials: L
authors.lastname: Jones
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Leon
authors.initials: L
authors.lastname: Thal
authors.forename: Michael
authors.initials: M
authors.lastname: Owen
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008923:Missouri; D020641:Polymorphism, Single Nucleotide; D012269:Ribosomal Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D005819:Genetic Markers; C031016:RPS3A protein, human; D012269:Ribosomal Proteins