Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme.
Linkage studies have suggested there is a susceptibility gene for late onset Alzheimer's disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin-degrading enzyme (IDE), a protease involved in the catabolism of Abeta. However, previous association studies have produced inconsistent results. To systematically evaluate the role of variation in IDE in the risk for LOAD, we genotyped 18 SNPs spanning a 276 kb region in and around IDE, including three "tagging" SNPs identified in an earlier study. We used four case-control series with a total of 1,217 cases and 1,257 controls. One SNP (IDE_7) showed association in two samples (P-value = 0.0066, and P = 0.026, respectively), but this result was not replicated in the other two series. None of the other SNPs showed association with LOAD in any of the tested samples. Haplotypes, constructed from the three tagging SNPs, showed no globally significant association. In the UK2 series, the CTA haplotype was over-represented in cases (P = 0.046), and in the combined data set, the CCG haplotype was more frequent in controls (P = 0.015). However, these weak associations observed in our series were in the opposite direction to the results in previous studies. Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD.
Nowotny
Petra
P
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
Hinrichs
Anthony L
AL
Smemo
Scott
S
Kauwe
John S K
JS
Maxwell
Taylor
T
Holmans
Peter
P
Hamshere
Marian
M
Turic
Dragana
D
Jehu
Luke
L
Hollingworth
Paul
P
Moore
Pamela
P
Bryden
Leslie
L
Myers
Amanda
A
Doil
Lisa M
LM
Tacey
Kristina M
KM
Gibson
Alison M
AM
McKeith
Ian G
IG
Perry
Robert H
RH
Morris
Chris M
CM
Thal
Leon
L
Morris
John C
JC
O'Donovan
Michael C
MC
Lovestone
Simon
S
Grupe
Andrew
A
Hardy
John
J
Owen
Michael J
MJ
Williams
Julie
J
Goate
Alison
A
D000483:Alleles; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007339:Insulysin / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D001057:Apolipoproteins E; D005819:Genetic Markers; D007339:Insulysin