Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants.
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).
Grupe
Andrew
A
Celera Diagnostics, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA.
Abraham
Richard
R
Li
Yonghong
Y
Rowland
Charles
C
Hollingworth
Paul
P
Morgan
Angharad
A
Jehu
Luke
L
Segurado
Ricardo
R
Stone
David
D
Schadt
Eric
E
Karnoub
Maha
M
Nowotny
Petra
P
Tacey
Kristina
K
Catanese
Joseph
J
Sninsky
John
J
Brayne
Carol
C
Rubinsztein
David
D
Gill
Michael
M
Lawlor
Brian
B
Lovestone
Simon
S
Holmans
Peter
P
O'Donovan
Michael
M
Morris
John C
JC
Thal
Leon
L
Goate
Alison
A
Owen
Michael J
MJ
Williams
Julie
J
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
D005819:Genetic Markers