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The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer's disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD. To explore this hypothesis, we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1, 256 SNPs in the NRXN1, NRXN2, NRXN3, and NLGN1 genes (3,009 cases and 3,006 control individuals). We identified a marker in the NRXN3 gene (rs17757879) that showed a consistent protective effect in all GWAS, however, the statistical significance obtained did not resist multiple testing corrections (OR = 0.851, p = 0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A combined meta-analysis of the former five GWAS together with a replication Spanish sample consisting of 1,785 cases and 1,634 controls confirmed this observation (rs17757879, OR = 0.742, 95% CI = 0.632-0.872, p = 0.00028, final meta-analysis). We conclude that NRXN3 might have a role in susceptibility to AD in males. [ABSTRACT FROM AUTHOR]

Background: In order to identify novel loci associated with Alzheimer's disease (AD), we conducted a genomewide association study (GWAS) in the Spanish population. Methods: We genotyped 1,128 individuals using the Affymetrix Nsp I 250K chip. A sample of 327 sporadic AD patients and 801 controls with unknown cognitive status from the Spanish general population were included in our initial study. To increase the power of the study, we combined our results with those of four other public GWAS datasets by applying identical quality control filters and the same imputation methods, which were then analyzed with a global meta-GWAS. A replication sample with 2,200 sporadic AD patients and 2,301 controls was genotyped to confirm our GWAS findings. Results: Meta-analysis of our data and independent replication datasets allowed us to confirm a novel genomewide significant association of AD with the membrane-spanning 4-domains subfamily A (MS4A) gene cluster (rs1562990, P = 4.40E-11, odds ratio = 0.88, 95% confidence interval 0.85 to 0.91, n = 10,181 cases and 14,341 controls). Conclusions: Our results underscore the importance of international efforts combining GWAS datasets to isolate genetic loci for complex diseases. [ABSTRACT FROM AUTHOR]

The MTHFD1L gene SNP variant rs11754661 was found to increase the risk of Alzheimer's disease in a recent Whole Genome Association Study [1]. We have carried out an independent study of this genetic variant in 2467 individuals from Spain. We found no evidence of association between the MTHFD1L marker and susceptibility to Alzheimer's disease in our sample. [ABSTRACT FROM AUTHOR]

GOLPH2 gene SNP variants Rs10868366 and Rs7019241 were reported to decrease the risk of Alzheimer's disease in a recent Whole Genome Association Study. We have investigated these genetic variants in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP markers. We found no evidence of association between GOLPH2 markers and susceptibility to Alzheimer's disease in our series. We concluded that GOLPH2 gene does not contribute to risk of disease in this study sample. [ABSTRACT FROM AUTHOR]

Abstract: Complement receptor 1 gene polymorphism rs3818361 was recently shown to increase the risk of Alzheimer’s disease (AD). We performed an independent replication study of this genetic variant in 2470 individuals from Spain. By applying an allelic model, we observed a trend toward an association between this marker and late-onset AD susceptibility in our case–control study (odds ratio = 1.114, 95% confidence interval: 0.958–1.296, P = .16). Meta-analysis of available studies (n = 31,771 individuals), including previous studies and public genome-wide association study resources (Alzheimer’s Disease Neuroimaging Initiative, Translational Genomics Research Institute, and Multi-site Collaborative Study for Genotype-Phenotype Associations in Alzheimer''s Disease), strongly supports the effect of rs3818361 (odds ratio = 1.180, 95% confidence interval: 1.113–1.252, P < 2.99E-8) and suggests the existence of between-study heterogeneity (P < .05). We concluded that the complement receptor 1 gene may contribute to AD risk, although its effect size could be smaller than previously estimated. [Copyright &y& Elsevier]

Abstract: The relationships between genome wide association study-identified and replicated genetic variants associated with Alzheimer''s disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. Seven hundred and one AD patients with at least 3 different cognitive evaluations and genotypic information for APOE and 6 genome wide association study-significant single-nucleotide polymorphisms were selected for this study. Mean differences in Global Deterioration Score and Mini Mental State Examination (MMSE) were evaluated using nonparametric tests, general linear model and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor, memantine, or both. Relationships between therapeutic protocols, genetic markers, and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared with GG carriers at the end of the follow-up (MMSE mean difference = −0.57; 95% confidence interval, −1.145 to 0.009; p = 0.047). This observation remained unaltered after covariate adjustments although it did not achieve predefined multiple testing significance threshold. The PICALM single-nucleotide polymorphism also displayed a significant effect protecting against rapid progression during pharmacogenetic assays although its observed effect displayed heterogeneity among AD therapeutic protocols (p = 0.039). None of the studied genetic markers were convincingly linked to AD progression or drug response. However, by using different statistical approaches, the PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes. [Copyright &y& Elsevier]

Abstract: The present research is aimed at assessing the role of 3 estrogen receptor alpha (ESR1) gene variants in late onset Alzheimer''s disease (AD) susceptibility. One thousand one hundred thirteen unrelated late onset sporadic AD patients, 1109 healthy controls and 121 neurologically healthy elderly controls were used to carry out case-control genetic association studies with ESR1 rs3844508, rs2234693, and ESR1 noncoding deletion 1 (ESR1-NCD1) polymorphisms. Thirty-five healthy male samples were used for molecular analyses. The rs2234693 polymorphism is associated with AD in our population (odds ratio [OR], 1.29; p = 0.008). The rs3844508 marker confers protection against AD in males (OR, 0.57; p = 0.001) and the deletion ESR1-NCD1 is a risk factor for AD in women (OR, 1.67; p < 0.001). Molecular analyses on ESR1-NCD1 indicate that this deletion confers a higher response to estradiol activity on ESR1 receptor and it is also associated with differential expression of ESR1 isoforms. Our results support the involvement of ESR1 gene in AD and point to the existence of sexual dimorphism for ESR1 markers. In addition, carriers of ESR1-NCD1 deletion could overrespond to estradiol action. [Copyright &y& Elsevier]