Genetic variants conferring susceptibility to Alzheimer’s disease in the general population; do they also predispose to dementia in Down’s syndrome

Ashok Patel,Simon D Rees,M Kelly,Anthony H Barnett,Humaria Arshad,Stephen C Bain,Anisha Prasher,Vee P Prasher

doi:10.1186/1756-0500-7-42

Abstract

BackgroundDown’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.ResultsThere 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.ConclusionsThis 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.

Highlights

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
DAD in DS One SNP was nominally associated with the development of DAD in DS; the PICALM rs561655 variant appeared to reduce the risk of DAD (HR = 0.72, p = 0.02; Table 1)
Six of the nine variants had hazard ratios greater than 1, none of these was significantly associated with the development of dementia (Table 1)

Summary

Introduction

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. A number of studies have shown that there is wide variation in the age of onset of dementia, from 38 to 70 years, with an average age at onset between 50 and 55 years [9,10] This variation may be explained by a number of factors, including methodological difficulties in diagnosis of DAD in this population [11], triplication of the beta-amyloid precursor protein (APP) gene [12], APOE genotypes [6,13], gender [14] and a number of unknown genetic variants

Results

Discussion

Conclusion