title: Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants.
abstract: This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case-control sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P = 6.94E - 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOEepsilon4 and epsilon2/3 variants (0.09 < D'<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P = 0.0010-0.00006; odds ratio (OR) = 1.07-1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P = 0.00005, OR = 1.2, false positive rate = 0.87).
authors.affiliation: Celera Diagnostics, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Grupe
authors.forename: Richard
authors.initials: R
authors.lastname: Abraham
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Li
authors.forename: Charles
authors.initials: C
authors.lastname: Rowland
authors.forename: Paul
authors.initials: P
authors.lastname: Hollingworth
authors.forename: Angharad
authors.initials: A
authors.lastname: Morgan
authors.forename: Luke
authors.initials: L
authors.lastname: Jehu
authors.forename: Ricardo
authors.initials: R
authors.lastname: Segurado
authors.forename: David
authors.initials: D
authors.lastname: Stone
authors.forename: Eric
authors.initials: E
authors.lastname: Schadt
authors.forename: Maha
authors.initials: M
authors.lastname: Karnoub
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: Kristina
authors.initials: K
authors.lastname: Tacey
authors.forename: Joseph
authors.initials: J
authors.lastname: Catanese
authors.forename: John
authors.initials: J
authors.lastname: Sninsky
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.forename: David
authors.initials: D
authors.lastname: Rubinsztein
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Brian
authors.initials: B
authors.lastname: Lawlor
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donovan
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Leon
authors.initials: L
authors.lastname: Thal
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005260:Female; D020868:Gene Silencing; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom; D014481:United States
chemical_list: D005819:Genetic Markers