Genetic variants conferring susceptibility to Alzheimer's disease in the general population; do they also predispose to dementia in Down's syndrome.
BACKGROUND
Down's syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer's disease (DAD) compared with the general population. Recent collaborative genome-wide association studies of large case control data sets of individuals with and without Alzhemier's disease (AD) have revealed new risk variants for dementia, as well as confirming previously identified risk variants. In this study, nine AD-derived SNPs, near or within the CR1 (rs3818361), BIN1 (rs744373), CD2AP (rs9349407), EPHA1 (rs11767557), CLU (rs1532278), MS4A6A/4A (rs610932), PICALM (rs561655), ABCA7 (rs3764650) and CD33 (rs3865444) genes were genotyped in 295 individuals with DS.


RESULTS
There were no significant associations between these nine GWAS-derived SNPs and DAD in British Caucasian individuals with DS. Interestingly the CR1 rs3818361 variant appeared to be associated with mortality in our cohort, particularly in the subjects without dementia. To our knowledge, this is the first time that this variant has been implicated as a determinant of mortality and the finding warrants further investigation in other cohorts with DS.


CONCLUSIONS
This study shows negative associations of nine AD-derived SNPs with DAD in DS. This may be due to the modest size of our cohort, which may indicate that our study is insufficiently powered to pick up such associations. We cannot conclusively exclude a role for these SNPs in DAD in DS. Clearly, efforts to investigate genetic variants with small effects on disease risk require a much larger cohort of individuals with DS. In fact, we hypothesize that a sample size of 4465 individuals with DS would be needed to determine the role in DAD in DS of the nine AD-derived SNPs investigated in this study. We therefore recommend that all national and international clinics with access to individuals with DS should contribute DNA samples to form DS consortia.
Department of Biomolecular and Sport Sciences, Faculty of Health and Life Sciences, Coventry University, Coventry, UK. ashok.patel@coventry.ac.uk.
Ashok
A
Patel
Simon D
SD
Rees
M Ann
MA
Kelly
Stephen C
SC
Bain
Anthony H
AH
Barnett
Anisha
A
Prasher
Humaria
H
Arshad
Vee P
VP
Prasher
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics*; D051152:Clusterin / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D003704:Dementia / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance / Q000379:methods; D011446:Prospective Studies; D036082:Receptor, EphA1 / Q000235:genetics; D017463:Receptors, Complement 3b / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; C114545:CD2-associated protein; C495242:CLU protein, human; C509991:CR1 protein, human; D051152:Clusterin; D003598:Cytoskeletal Proteins; C424714:MS4A4A protein, human; C574492:MS4A6A protein, human; D008565:Membrane Proteins; D034041:Monomeric Clathrin Assembly Proteins; D009687:Nuclear Proteins; C439003:PICALM protein, human; D017463:Receptors, Complement 3b; D025521:Tumor Suppressor Proteins; D036082:Receptor, EphA1