Jordi Clarimón

Instituto de Salud Carlos III, Madrid, Madrid, Spain

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Publications (92)448.94 Total impact

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    ABSTRACT: Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.
    Neurobiology of Aging 12/2014; · 6.17 Impact Factor
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    ABSTRACT: Purpose Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common childhood epileptic syndrome. Different mutations in genes that control the excitability of neurons have been described. Recent reports on the involvement of the BDNF and ELP4 genes in cell motility, migration, and adhesion raise the possibility that these genes are involved in pathogenesis of BECTS. Materials and methods we conducted a case-control association study on 60 patients with BECTS and 60 control participants to assess the influence of the BDNF and ELP4 polymorphisms on BECTS. The polymorphisms were detected with a PCR-RFLP method. Moreover, we explored the possible association of these polymorphisms with clinical and electroencephalographic parameters of patients with BECTS. Results Our results show no difference in BDNF and ELP4 genotype frequencies between patients and controls. Haplotype analysis also revealed no statistical difference. Conclusion the role of BDNF and ELP4 polymorphisms remains controversial.
    Epilepsy Research. 09/2014;
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    ABSTRACT: In this study we found that patients with C9orf72 repeat expansion showed cerebellar and posterior brain hypometabolism as compared to bvFTD non-carriers. Our results suggest that impairment in cerebellar and parietal glucose metabolism may be a feature of some cases with the C9orf72 repeat expansion. Importantly, the two carriers of the C9orf72 repeat expansion were in the early stages of bvFTD and the symptoms were mild at the time of brain scanning. This suggests that changes in glucose metabolism may be an early feature that may precede dementia. Although the structural imaging patterns associated to the C9orf72 expansion have been widely described, functional imaging studies are limited. To date, Boeve et al.3 reported the 18F-FDG PET findings in 5 patients carrying the C9orf72 expansion. Four of them showed predominantly anterior cingulate hypometabolism, while the other had parietal hypometabolism, with sparing of frontal cortical regions. Savica et al.4 described a family carrying the C9orf72 expansion, and 18F-FDG PET showed mild hypometabolism in frontotemporal regions, but normal in parietal cortices. Recently, Devenney et al.9 reported 6 patients with bvFTD carrying the C9orf72 expansion. Most had a typical frontal and temporal hypometabolism, but two also showed parietal hypometabolism and one had cerebellar hypometabolism. Additionally, Cistaro et al.6 found that ALS cases with the C9orf72 expansion had cerebellar hypermetabolism compared to healthy controls but not compared to sporadic ALS cases. Hypometabolism in posterior brain regions has also been described in SLE patients with neuropsychiatric symptoms.10 Therefore, we cannot completely exclude that SLE contributed to some of the findings in brain metabolism observed in case 2. MRI findings in the two C9orf72 expansion carriers presented herein are in agreement with previous studies,3–5 showing a pattern of parietal and cerebellar atrophy that differentiate them from sporadic bvFTD patients or from those carrying a MAPT or GRN mutation.5 The presence of cerebellar atrophy on MRI or hypometabolism in 18F-FDG PET (described herein) is an intriguing finding since cerebellar symptoms are not usually present in C9orf72 mutation carriers. Only one patient with cerebellar symptoms has been reported in the literature in a family with genetic linkage within the chromosome 9p region.11 None of our two cases had either cerebellar symptoms or signs on neurological examination. Interestingly, the neuropathology of patients carrying the C9orf72 expansion typically includes cerebellar atrophy with ubiquitinated p62-positive TDP-43 negative inclusions.12 Whether these pathological findings have any relationship with 18F-FDG PET hypometabolism reported here remains to be established. The imaging findings reported herein were found in two patients from a highly selected population and they need to be confirmed in larger series of patients with bvFTD with the C9orf72 expansion. Whether cerebellar hypometabolism is present in most subjects with bvFTD and C9orf72 or only in a subset of them also needs to be determined. If confirmed, the presence of cerebellar abnormalities in 18F-FDG PET in a patient with bvFTD might be a sign of suspicion of a C9orf72 expansion.
    Alzheimer Disease and Associated Disorders 09/2014; · 2.73 Impact Factor
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    ABSTRACT: BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. INTERPRETATION: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD
    The Lancet Neurology 07/2014; 3(7):686-99. · 23.92 Impact Factor
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    ABSTRACT: Background: Alzheimer’s disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer’s Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer’s cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p=1.461026) and 14 (IGHV1-67 p=7.961028) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer’s disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer’s disease
    PLoS ONE 06/2014; 9(6):e94661. · 3.53 Impact Factor
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    ABSTRACT: Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.
    Acta Neuropathologica 06/2014; · 9.73 Impact Factor
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    ABSTRACT: Objective: To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer's Disease (AD). Methods: Cross-sectional study. Normal controls (n=145) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent structural 3T-MRI and lumbar puncture. CSF amyloid 1-42 (Aß1-42 ) and phospho-tau (p-tau181p ) levels were measured by Luminex assays. Samples were dichotomized using published cut-offs (Aß+/Aß- and p-tau+/ptau-). CTh was measured by Freesurfer. CTh difference maps were derived from interaction and correlation analyses. Clusters from the interaction analysis were isolated to analyze the directionality of the interaction in an ANCOVA analysis. Results: We found a significant biomarker interaction between CSF Aß1-42 and CSF p-tau181p levels on brain structure. Cortical atrophy only occurs in subjects with both Aß+ and p-tau+. The stratified correlation analyses showed that the relationship between p-tau181p and CTh is modified by Aß1-42 status and the relationship between Aß1-42 and CTh is modified by p-tau181p status. P-tau181p dependent thinning was found in different cortical regions in Aß+ subjects but not in Aß- subjects. Cortical thickening was related to decreasing CSF Aß1-42 values in the absence of abnormal p-tau181p , but no correlations were found in p-tau+ subjects. Interpretation: Our data suggest that interactions between biomarkers in AD result in a two-phase phenomenon of pathological cortical thickening associated with low CSF Aß1-42, followed by atrophy once CSF p-tau181p becomes abnormal. These interactions should be considered in clinical trials in preclinical AD, both when selecting patients and when using MRI as a surrogate marker of efficacy. ANN NEUROL 2014. © 2014 American Neurological Association.
    Annals of Neurology 05/2014; · 11.19 Impact Factor
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    ABSTRACT: Background: Biomarkers in the cerebrospinal fluid (CSF) can track specific pathophysiological pathways underlying Alzheimer's disease (AD). The connection between these biomarkers remains unclear. Objective: To study six CSF biomarkers in a clinical cohort of patients with different neurodegenerative conditions. Methods: We measured markers of amyloid-β protein precursor (AβPP) processing (Aβ42, sAβPPβ, β-secretase activity), neuronal damage (total tau, p-tau), and inflammation (YKL-40) in CSF from 194 participants with the following diagnoses: subjective cognitive impairment or non-amnestic mild cognitive impairment (na-SCI, n = 44), amnestic mild cognitive impairment (aMCI, n = 45), dementia of the Alzheimer type (DAT, n = 59), frontotemporal dementia (FTD, n = 22), and 24 cognitively normal controls. We compared biomarkers between clinical groups and CSF-profile groups, and we analyzed the correlation between biomarkers. Results: CSF levels of sAβPPβ were decreased in FTD patients compared to the other groups. YKL-40 was elevated in DAT and FTD, and also in aMCI patients with evidence of the AD pathophysiological process. CSF Aβ42 correlated positively with β-secretase activity (RS = 0.262) and sAβPPβ (RS = 0.341). CSF YKL-40 correlated positively with total tau (RS = 0.467) and p-tau (RS = 0.429). CSF p-tau and sAβPPβ contributed significantly to distinguish DAT from FTD. Conclusions: CSF biomarkers of AβPP processing correlate with each other and are decreased in FTD. The inflammatory marker YKL-40 is increased in different neurodegenerative diseases, even in early stages, and it correlates with biomarkers of neurodegeneration. This suggests that inflammation is a common feature in AD and FTD. A combination of CSF biomarkers tracking distinct pathophysiological processes may be useful to classify subjects with neurodegenerative conditions.
    Journal of Alzheimer's disease: JAD 05/2014; · 4.17 Impact Factor
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    ABSTRACT: Objective:To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer's Disease (AD).Methods:Cross-sectional study. Normal controls (n=145) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent structural 3T-MRI and lumbar puncture. CSF amyloid 1-42 (Aß1-42) and phospho-tau (p-tau181p) levels were measured by Luminex assays. Samples were dichotomized using published cut-offs (Aß+/Aß- and p-tau+/ptau-). CTh was measured by Freesurfer. CTh difference maps were derived from interaction and correlation analyses. Clusters from the interaction analysis were isolated to analyze the directionality of the interaction in an ANCOVA analysis.Results:We found a significant biomarker interaction between CSF Aß1-42 and CSF p-tau181p levels on brain structure. Cortical atrophy only occurs in subjects with both Aß+ and p-tau+. The stratified correlation analyses showed that the relationship between p-tau181p and CTh is modified by Aß1-42 status and the relationship between Aß1-42 and CTh is modified by p-tau181p status. P-tau181p dependent thinning was found in different cortical regions in Aß+ subjects but not in Aß- subjects. Cortical thickening was related to decreasing CSF Aß1-42 values in the absence of abnormal p-tau181p, but no correlations were found in p-tau+ subjects.Interpretation:Our data suggest that interactions between biomarkers in AD result in a two-phase phenomenon of pathological cortical thickening associated with low CSF Aß1-42, followed by atrophy once CSF p-tau181p becomes abnormal. These interactions should be considered in clinical trials in preclinical AD, both when selecting patients and when using MRI as a surrogate marker of efficacy. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 05/2014; · 11.19 Impact Factor
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    ABSTRACT: Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer's disease (AD). One of the most strongly nitrotyrosinated proteins in AD, the triosephosphate isomerase (TPI) enzyme, regulates glycolytic flow, which decreases its efficiency. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we evaluated the effects of Aβ42 oligomers on TPI nitrotyrosination. We found an increased production of methylglyoxal (MG), a toxic byproduct of the inefficient nitro-TPI function. The proapoptotic effects of Aβ42 oligomers, such as decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax, were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F and Y209F) to mimic nitrosative modifications due to Aβ action. Neuroblastoma cells transfected with the double mutant TPI consistently triggered MG production and a decrease in cell viability due to apoptotic mechanisms. Our data show for the first time that MG is playing a key role in the neuronal death induced by Aβ oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center.
    Journal of Alzheimer's disease: JAD 03/2014; · 4.17 Impact Factor
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    ABSTRACT: Several reports suggest that the reelin protein could play a role in Alzheimer pathophysiology. This led us to ask whether genetic variability in the reelin pathway may increase the risk of developing Alzheimer disease (AD) or mild cognitive impairment (MCI). This was a case-control study in which neuropsychological tests were administered and peripheral blood samples taken. The study included 121 patients with AD, 94 with MCI, and 198 controls. Forty biallelic variants single nucleotide polimorphisms were genotyped in 8 genes related to reelin signaling pathway using a SNPlex genotyping system, and allele frequencies were compared between patients and controls using χ tests and obtaining odds ratios (OR). A total of 413 subjects with complete neuropsychological data were analyzed. A significant association between the genotypes RELN (rs528528 and rs2299356), PLK2 (rs15009 and rs702723), and CAMK2A (rs3756577 and rs3822606) and AD or MCI was found. A significant association also was found between the GG genotype at the RELN-rs2299356 and the risk of AD (OR=2.68, P=0.003) and between the AG genotype at the CAMK2A-rs3822606 (OR=2.13, P=0.004). We found a protective effect of the RELN-rs528528 CT genotype and MCI (OR=0.36, P=0.002), and the PLK2-rs15009 CC and GG genotypes and CC genotype at PLK2-rs702723 with OR ranging from 0.40 to 0.57 on AD. These data suggest that TT or CT genotypes at CAMK2A-rs3756577 is associated with risk reduction for AD and MCI ranging from 2 to nearly 8 times. Our data suggest a possible relation between certain reelin signaling pathway genotypes and cognitive impairment related to AD.
    Alzheimer disease and associated disorders 12/2013; · 2.88 Impact Factor
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    Dataset: ng.2802
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    ABSTRACT: About a half of patients with frontotemporal dementia (FTD) has deposition of phosphorylated TDP-43 protein (pTDP-43) in the brain. We studied pTDP-43 and total TDP-43 levels in plasma and cerebrospinal fluid (CSF) in healthy controls and patients with FTD, including those carrying a repeat expansion in the C9orf72 gene or a mutation in GRN. We included 88 plasma samples of 10 C9orf72 expansion carriers, 5 GRN mutation carriers, 51 patients with FTD without a known mutation and 22 healthy controls. We also obtained CSF samples from 25 patients with FTD (2 with C9orf72 expansion and 3 with a GRN mutation) and 22 healthy controls. We measured pTDP-43 and total TDP-43 levels using sandwich ELISA. Patients carrying the C9orf72 repeat expansion or a GRN mutation had significantly higher plasma and CSF levels of pTDP-43 than the remaining patients with FTD (p<0.05). In addition, plasma pTDP-43 levels were higher in patients with FTD carrying a C9orf72 expansion or GRN mutations than in healthy controls (p<0.05). Our study shows that plasma pTDP-43 levels may be increased in some genetic forms of FTD known to be associated with TDP-43 proteinopathies.
    Journal of neurology, neurosurgery, and psychiatry 12/2013; · 4.87 Impact Factor
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    Jordi Clarimón, Jaime Kulisevsky
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    ABSTRACT: Breakthroughs in genetics over the last decade have radically advanced our understanding of the etiological basis of Parkinson's disease (PD). Although much research remains to be done, the main genetic causes of this neurodegenerative disorder are now partially unraveled, allowing us to feel more confident that our knowledge about the genetic architecture of PD will continue to increase exponentially. How and when these discoveries will be introduced into general clinical practice, however, remains uncertain. In this review, we provide a general summary of the progress in the genetics of PD and discuss how this knowledge will contribute to the diagnosis and clinical management of patients with, or at risk of this disorder.
    Current Genomics 12/2013; 14(8):560-7. · 2.48 Impact Factor
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    ABSTRACT: Dementia with Lewy bodies (DLB) is pathologically characterized by α-synuclein aggregates in the brain. Most patients with DLB also show cerebral Alzheimer disease-type pathology (i.e. β-amyloid plaques and hyperphosphorylated tau deposits). It is unclear whether this overlap is coincidental or driven by specific regional or cellular interactions. The aims of this study were to investigate the regional convergence of α-synuclein, tau, and β-amyloid and to identify patterns of cellular co-occurrence of tau and α-synuclein in DLB. The study group consisted of 22 patients who met clinical and neuropathologic criteria for DLB. Protein aggregates were assessed semiquantitatively in 17 brain areas. APOE and MAPT genotypes were determined. Cellular co-occurrence of tau and α-synuclein was evaluated by double immunofluorescence. We found that total β-amyloid pathology scores correlated positively with total α-synuclein pathology scores (ρ = 0.692, p = 0.001). The factors that correlated best with the amount of α-synuclein pathology were the severity of β-amyloid pathology and presence of the MAPT H1 haplotype. Tau and α-synuclein frequently colocalized in limbic areas, but no correlation between total pathology scores was observed. This study confirms and extends the role of β-amyloid deposition and the MAPT H1 haplotype as contributing factors in DLB pathogenesis and demonstrates the confluence of multiple agents in neurodegenerative diseases.
    Journal of neuropathology and experimental neurology. 11/2013;
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    ABSTRACT: Autosomal-dominant Alzheimer's disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on APP mutations to-date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD-associated APP I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO-K1 cells. All APP I716 mutations increased the ratio of Aβ42/40 and changed the product line preference of γ-secretase towards Aβ38 production. In addition, the APP I716F mutation impaired the ε-cleavage and the fourth cleavage of γ-secretase and led to abnormal APP β-CTF accumulation at the plasma membrane. Taken together, these data indicate that APP mutations at the same codon can induce diverse abnormalities in APP processing, some resembling PSEN1 mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different APP mutations at the same position. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 10/2013; · 3.97 Impact Factor
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    ABSTRACT: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
    Nature Genetics 10/2013; · 35.21 Impact Factor
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    ABSTRACT: Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of more than 30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P<0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's Rho=0.743, P=1.05 x 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.
    Human Molecular Genetics 09/2013; · 7.69 Impact Factor
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    ABSTRACT: Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer's disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca(2+) influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+) influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.
    PLoS ONE 09/2013; 8(9):e74203. · 3.53 Impact Factor
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    ABSTRACT: 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.
    Neurobiology of aging 09/2013; · 5.94 Impact Factor

Publication Stats

1k Citations
448.94 Total Impact Points

Institutions

  • 2011–2014
    • Instituto de Salud Carlos III
      Madrid, Madrid, Spain
  • 2008–2014
    • Hospital de la Santa Creu i Sant Pau
      Barcino, Catalonia, Spain
    • Hospital Universitari i Politècnic la Fe
      Valenza, Valencia, Spain
  • 2003–2013
    • University Pompeu Fabra
      • Department of Experimental and Health Sciences
      Barcelona, Catalonia, Spain
  • 2012
    • Hospital 12 de Octubre
      Madrid, Madrid, Spain
    • IPHES Catalan Institute for Human Palaeoecology and Social Evolution
      Tarraco, Catalonia, Spain
  • 2011–2012
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
  • 2010–2012
    • Centro de Investigación Biomédica en Red, Enfermedades Neurodegenerativas
      Madrid, Madrid, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
      Barcino, Catalonia, Spain
  • 2004–2008
    • National Institutes of Health
      • Laboratory of Neurogenetics
      Bethesda, MD, United States
  • 2005–2007
    • National Institute on Aging
      • Laboratory of Neurogenetics (LNG)
      Baltimore, Maryland, United States