Genome-wide significant risk factors on chromosome 19 and the APOE locus.

The apolipoprotein E () gene on chromosome 19q13.32, was the first, and remains the strongest, genetic risk factor for Alzheimer's disease (AD). Additional signals associated with AD have been located in chromosome 19, including (19p13.3) and 19q13.41). The gene has been replicated in most populations. However, the contribution to AD of other signals close to gene remains controversial. Possible explanations for inconsistency between reports include long range linkage disequilibrium (LRLD). We analysed the contribution of and loci to AD risk and explore LRLD patterns across region. To evaluate AD risk conferred by rs4147929:G>A and rs3865444:C>A, we used a large Spanish population (1796 AD cases, 2642 controls). The rs4147929:G>A SNP effect was nominally replicated in the Spanish cohort and reached genome-wide significance after meta-analysis (odds ratio (OR)=1.15, 95% confidence interval (95% CI)=1.12-1.19; = 1.60 x 10). rs3865444:C>A was not associated with AD in the dataset. The meta-analysis was also negative (OR=0.98, 95% CI=0.93-1.04; =0.48). After exploring LRLD patterns between and in several datasets, we found significant LD (D' >0.20; <0.030) between -Ɛ2 and rs3865444C>A in two of five datasets, suggesting the presence of a non-universal long range interaction between these loci affecting to some populations. In conclusion, we provide here evidence of genetic association of the locus in the Spanish population and also propose a plausible explanation for the controversy on the contribution of to AD susceptibility.