Genetic Analysis of Alzheimer’s Disease in the Uppsala Longitudinal Study of Adult Men

Abstract

Background/Aims: Genetic factors influencing common complex conditions have proven difficult to identify, and data from numerous investigations have provided incomplete conclusions as to the identity of these genes. Here we aimed to identify susceptibility genes for late-onset Alzheimer’s disease (AD). Methods: The case-control analysis included samples from 86 AD patients and 404 cognitively healthy controls selected from the Uppsala Longitudinal Study of Adult Men (ULSAM). In the incidence analysis, all 1,088 genotyped ULSAM participants were included. DNA samples from ULSAM participants were analyzed for 2,578 single nucleotide polymorphisms (SNP) within 368 genes. The selection of genes tested for association to AD within this cohort was based on genes previously implicated in conditions with relevance to ULSAM, such as dementia, cardiovascular disease, diabetes and metabolic syndrome, osteoporosis, and cancer. Results/Conclusion: Association analysis revealed 82 genes containing at least 1 significant SNP at p < 0.05 with association to AD. Only 20 genes remained significant after a permutation test to correct for multiple comparisons within individual genes. Using publicly available data from 2 genome-wide association (GWA) studies and linkage disequilibrium data from HapMap, we attempted to replicate the AD association identified in ULSAM. In addition to apolipoprotein E, we were able to replicate 5 other genes in both GWA studies at p < 0.05.

Lack of association between MTHFR A1298C variant and Alzheimer’s disease: evidence from a systematic review and cumulative meta-analysis

“…Thus, 118 publications were futher excluded. Finally, 10 eligible studies [16,19,[21][22][23][24][25][26][27][28] were recognized in this meta-analysis. The main characteristics of all these studies are listed in Table 1.…”

“…Several studies [16,19,[21][22][23][24][25][26][27][28] tried to find out any association between MTHFR A1298C polymorphism and the risk of AD; due to different populations, case selections, and sample sizes, the association remained inconclusive. Two articles [16,25] revealed the genetic association of MTHFR A1298C polymorphism with AD risk, but others indicated lack of this association.…”

Estrogen receptor polymorphisms and incident dementia: The prospective 3C study

“…Other case-control studies have found no significant associations [12][13][14], although the small sample sizes in several cases meant a lack of statistical power.…”

“…Of the few prior case-control studies which have examined ESR2 polymorphisms [13,21,29,42,43], rs4986938 is the only one common to multiple studies. In keeping with our findings, they report no independent association between AD prevalence and rs4986938.…”

“…Some of these studies have reported that AD patients had a significantly higher frequency of the minor C and G alleles of rs2234693 and rs9340799 respectively [8][9][10][11], yet other studies have found no significant associations [12][13][14] or even reverse associations [15,16]. Meta-analyses conducted a few years ago found a small but significant association between the minor alleles of these polymorphisms and an increased risk of AD (OR~1.2) [17,18], however this is not supported by the most recent metaanalysis on the Alzheimer's Research Forum (http://www.alzgene.org).…”