University Hospital la Paz Cantoblanco

Madrid, Spain

University Hospital la Paz Cantoblanco

Madrid, Spain

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Ruiz A.,Institute Catala Of Neurociencies Aplicades | Ruiz A.,University of Bonn | Heilmann S.,University of Bonn | Becker T.,German Center for Neurodegenerative Diseases | And 50 more authors.
Translational Psychiatry | Year: 2014

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10 - 9). © 2014 Macmillan Publishers Limited All rights reserved.


Boada M.,Institute Catala Of Neurociencies Aplicades | Boada M.,Autonomous University of Barcelona | Antunez C.,University of Murcia | Ramirez-Lorca R.,NeoCodex | And 37 more authors.
Molecular Psychiatry | Year: 2014

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10-6 were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10 -7 in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10 -9). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation. © 2014 Macmillan Publishers Limited.


Lambert J.-C.,French Institute of Health and Medical Research | Lambert J.-C.,University of Lille Nord de France | Sleegers K.,Neurodegenerative Brain Diseases Group | Sleegers K.,University of Antwerp | And 81 more authors.
Journal of Alzheimer's Disease | Year: 2010

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene. © 2010 IOS Press and the authors. All rights reserved.


Antunez C.,University of Murcia | Antunez C.,Alzheimur Foundation | Boada M.,Institute Catala Of Neurociencies Aplicades | Boada M.,Autonomous University of Barcelona | And 36 more authors.
Genome Medicine | Year: 2011

Background: In order to identify novel loci associated with Alzheimer's disease (AD), we conducted a genome-wide 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 genome-wide 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. © 2011 Antúnez et al.; licensee BioMed Central Ltd.


Boada M.,Institute Catala Of Neurociencies Aplicades | Boada M.,University of Barcelona | Antunez C.,University of Murcia | Antunez C.,Alzheimur Foundation | And 14 more authors.
Journal of Alzheimer's Disease | Year: 2010

CALHM1 gene coding non-synonymous SNP P86L (rs2986017) was reported to increase the risk of Alzheimer's disease (AD) in a recent study. We have investigated this genetic variant in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP marker. By applying a recessive model, we observed weak evidence of an association between P86L mutation and late-onset AD (LOAD) susceptibility in our case-control study (OR =1.38 C.I. = [1.01-1.89]). Meta-analysis of available studies also supports a recessive model for CALHM1 P86L variant and provides evidence of between study heterogeneity. Importantly, we found that adjusted mean age at AD onset in P86L homozygous LOAD patients was significantly earlier that in the rest of patients (77.01 ± 6.1 for P86L homozygous carriers versus 79.0 ± 6.0 for the rest of patients, p=0.002). We concluded that the CALMH1 gene may contribute to AD risk in our study population. The observed genetic model (recessive) and the estimated magnitude of the effect both imply that virtually all studies performed to date were markedly underpowered to detect this effect and underscore the importance of follow up, replication, and meta-analyses of promising genetic signals. © 2010 - IOS Press and the authors.


Moreno-Grau S.,Institute Catala Of Neurociencies Aplicades | Moreno-Grau S.,Institute Of Recerca Of Lhospital Universitari Of La Vall Dhebron Vhir | Barneda B.,Institute Of Recerca Of Lhospital Universitari Of La Vall Dhebron Vhir | Barneda B.,Autonomous University of Barcelona | And 26 more authors.
Journal of Alzheimer's Disease | Year: 2015

The objective of this study was to identify genetic variation in genes encoding death receptors and signals that modulate their activity. After conducting a meta-analysis with five previous genome-wide association studies and aggregated data, the most significant signals, (TNF locus: rs2395488, rs2534672, and rs9267445; and FASLG locus: rs730278), were replicated in 1,046 cases and 372 controls. The rs2395488 and rs2534672 markers showed a modest protective effect (OR = 0.849, p = 0.49780; OR = 0.687, p = 0.11335), in contrast to rs730278 marker (OR = 1.146, p = 0.17212), which did not follow the previous effect direction; in any case it reached the significance level. Final meta-analysis, adding the replication sample, confirmed these observations. We concluded that FASLG marker is not etiologically linked to Alzheimer's disease. However, single nucleotide polymorphisms around TNF locus require further analyses in order to explain the association between Alzheimer's disease and human leukocyte antigen. © 2015 - IOS Press and the authors. All rights reserved.


Ruiz A.,Institute Catala Of Neurociencies Aplicades | Dols-Icardo O.,Autonomous University of Barcelona | Dols-Icardo O.,CIBER ISCIII | Bullido M.J.,CIBER ISCIII | And 45 more authors.
Neurobiology of Aging | Year: 2014

A non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimer's disease (AD). Also, rare recessive mutations have been associated with frontotemporal dementia (FTD). We aimed to investigate the role of p.R47H variant in AD and FTD through a multi-center study comprising 3172 AD and 682 FTD patients and 2169 healthy controls from Spain. We found that 0.6% of AD patients carried this variant compared to 0.1% of controls (odds ratio [OR]= 4.12, 95% confidence interval [CI]= 1.21-14.00, p= 0.014). A meta-analysis comprising 32,598 subjects from 4 previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR= 4.11, 95% CI= 2.99-5.68, p= 5.27×10-18). We did not find an association between p.R47H and age of onset of AD or family history of dementia. Finally, none of the FTD patients harbored this genetic variant. These data strongly support the important role of p.R47H in AD risk, and suggest that this rare genetic variant is not related to FTD. © 2014 Elsevier Inc.


Ramirez-Lorca R.,NeoCodex | Boada M.,Institute Catala Of Neurciencies Aplicades | Boada M.,Autonomous University of Barcelona | Antunez C.,University of Murcia | And 11 more authors.
Journal of Alzheimer's Disease | Year: 2011

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. © 2011 - IOS Press and the authors. All rights reserved.


Antunez C.,University of Murcia | Antunez C.,AlzheimUr Foundation | Boada M.,Institute Catal Of Neurcincies Aplicades | Boada M.,Autonomous University of Barcelona | And 11 more authors.
Alzheimer's and Dementia | Year: 2011

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. © 2011 The Alzheimer's Association. All rights reserved.

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