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52. Genome-wide association study indentifies variants at CLU and CR1 associated with Alzheimer’s disease

Author

Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, European Alzheimer's Disease Initiative Investigators, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P, FORTI, PAOLA, Lambert, J, Heath, S, Even, G, Campion, D, Sleegers, K, Hiltunen, M, Cambarros, O, Zelenika, D, Bullido, M, Tavernier, B, Letenneur, L, Bettens, K, Berr, C, Pasquier, F, Fiévet, N, Barbager Gateau, P, Engelborghs, S, De Deyn, P, Mateo, I, Franck, A, Helisalmi, S, Porcellini, E, Hanon, O, the European Alzheimer’s disease Initiative, I, de Pancorbo, M, Lendon, C, Dufouil, C, Jaillard, C, Leveillard, T, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Piccardi, P, Annoni, G, Seripa, D, Galimberti, D, Hannequin, D, Licastro, F, Soininen, H, Ritchie, K, Blanché, H, Dartigues, J, Tzourio, C, Gut, I, Broeckhoven, C, Alpérovitch, A, Lathrop, M, Amouyel, P, Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, European Alzheimer's Disease Initiative Investigator, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P, Electronics and Informatics, Clinical sciences, Neurology, and Pathologic Biochemistry and Physiology

Subjects
Apolipoprotein E, SORL1, Genome-wide association study, Disease, Polymorphism, Single Nucleotide, White People, ABCA7, PICALM, Alzheimer Disease, Genetics, Humans, Genetic Predisposition to Disease, European Continental Ancestry Group/genetics, Alzheimer's disease, genome-wide association, APOE, APOJ, Medicine(all), Alzheimer Disease/genetics, biology, Phosphatidylinositol binding, Clusterin, Haplotypes, Receptors, Complement 3b, biology.protein, Human medicine, Clusterin/genetics, Receptors, Complement 3b/genetics, Genome-Wide Association Study
Abstract

The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P 10 5) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81-0.90, P = 7.5 × 10 9 for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14-1.29, P = 3.7 × 10 9 for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of Β amyloid (AΒ) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease. © 2009 Nature America, Inc. All rights reserved.

Published
2009

53. Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia

Author

Ruiz A, Dols-Icardo O, Bullido MJ, Pastor P, Rodríguez-Rodríguez E, López de Munain A, de Pancorbo MM, Pérez-Tur J, Alvarez V, Antonell A, López-Arrieta J, Hernández I, Tárraga L, Boada M, Lleó A, Blesa R, Frank-García A, Sastre I, Razquin C, Ortega-Cubero S, Lorenzo E, Sánchez-Juan P, Combarros O, Moreno F, Gorostidi A, Elcoroaristizabal X, Baquero M, Coto E, Sánchez-Valle R, Clarimón J, and dementia genetic Spanish consortium (DEGESCO)

Subjects
mental disorders, Alzheimer's disease, Frontotemporal dementia, Genetic association, Rare variant, TREM2, p.R47H
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.

Published
2014

54. Novel mutation of SACS gene in a Spanish family with autosomal recessive spastic ataxia

Author

CRISCUOLO, CHIARA, SACCA', FRANCESCO, DE MICHELE, GIUSEPPE, FILLA, ALESSANDRO, MANCINI P, COMBARROS O, INFANTE J, GARCIA A, BANFI S, BERCIANO J., Criscuolo, C, Sacca, F, De Michele, G, Mancini, P, Combarros, O, Infante, J, Garcia, A, Banfi, Sandro, Filla, A, Berciano, J., Criscuolo, Chiara, Sacca', Francesco, DE MICHELE, Giuseppe, Banfi, S, and Filla, Alessandro

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disorder characterized by early-onset, spastic ataxia and peripheral neuropathy. It was originally described in an inbred population of Quebec and later in some other countries. We report a new missense SACS mutation (7848C>T) in a Spanish family whose phenotype is similar to that of the previously described ARSACS patients. 7848C>T is the first SACS mutation reported in Spain confirming worldwide distribution of the disease. (c) 2005 Movement Disorder Society.

Published
2005

55. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk

Author

Sanchez-Juan, P. (Pascual), Bishop, M.T. (Matthew), Kovacs, G.G. (Gabor), Calero, M. (Miguel), Aulchenko, Y.S. (Yurii), Ladogana, A. (Anna), Boyd, A. (Alison), Lewis, V. (Victoria), Ponto, C. (Claudia), Calero, O. (Olga), Poleggi, A. (Anna), Carracedo, A. (Angel), Lee, S.J. (Sven) van der, Ströbel, T. (Thomas), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Haik, S., Combarros, O. (Onofre), Berciano, J. (José), Uitterlinden, A.G. (André), Collins, S.J. (Steven), Budka, H. (Herbert), Brandel, J-P. (Jean-Philippe), Laplanche, J.-L. (Jean-Louis), Pocchiari, M. (Maurizio), Zerr, I. (Inga), Knight, R. (Richard), Will, R.G. (Robert), Duijn, C.M. (Cornelia) van, Sanchez-Juan, P. (Pascual), Bishop, M.T. (Matthew), Kovacs, G.G. (Gabor), Calero, M. (Miguel), Aulchenko, Y.S. (Yurii), Ladogana, A. (Anna), Boyd, A. (Alison), Lewis, V. (Victoria), Ponto, C. (Claudia), Calero, O. (Olga), Poleggi, A. (Anna), Carracedo, A. (Angel), Lee, S.J. (Sven) van der, Ströbel, T. (Thomas), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Haik, S., Combarros, O. (Onofre), Berciano, J. (José), Uitterlinden, A.G. (André), Collins, S.J. (Steven), Budka, H. (Herbert), Brandel, J-P. (Jean-Philippe), Laplanche, J.-L. (Jean-Louis), Pocchiari, M. (Maurizio), Zerr, I. (Inga), Knight, R. (Richard), Will, R.G. (Robert), and Duijn, C.M. (Cornelia) van

Abstract

We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls

Published
2015
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56. A Genome Wide Association Study Links Glutamate Receptor Pathway to Sporadic Creutzfeldt-Jakob Disease Risk

Author

Zanusso, G, Sanchez-Juan, P, Bishop, MT, Kovacs, GG, Calero, M, Aulchenko, YS, Ladogana, A, Boyd, A, Lewis, V, Ponto, C, Calero, O, Poleggi, A, Carracedo, A, van der Lee, SJ, Stroebel, T, Rivadeneira, F, Hofman, A, Haik, S, Combarros, O, Berciano, J, Uitterlinden, AG, Collins, SJ, Budka, H, Brandel, J-P, Louis Laplanche, J, Pocchiari, M, Zerr, I, Knight, RSG, Will, RG, van Duijn, CM, Zanusso, G, Sanchez-Juan, P, Bishop, MT, Kovacs, GG, Calero, M, Aulchenko, YS, Ladogana, A, Boyd, A, Lewis, V, Ponto, C, Calero, O, Poleggi, A, Carracedo, A, van der Lee, SJ, Stroebel, T, Rivadeneira, F, Hofman, A, Haik, S, Combarros, O, Berciano, J, Uitterlinden, AG, Collins, SJ, Budka, H, Brandel, J-P, Louis Laplanche, J, Pocchiari, M, Zerr, I, Knight, RSG, Will, RG, and van Duijn, CM

Abstract

We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis.

Published
2015

57. A Genome Wide Association Study Links Glutamate Receptor Pathway to Sporadic Creutzfeldt-Jakob Disease Risk

Author

Sanchez-Juan, P, Bishop, MT, Kovacs, GG, Calero, M, Aulchenko, YS, Ladogana, A, Boyd, A, Lewis, V, Ponto, C, Calero, O, Poleggi, A, Carracedo, A, van der Lee, Sven, Strobel, T, Rivadeneira, Fernando, Hofman, Bert, Haik, S, Combarros, O, Berciano, J, Uitterlinden, André, Collins, SJ, Budka, H, Brandel, JP, Laplanche, JL, Pocchiari, M, Zerr, I, Knight, RSG, Will, RG, Duijn, Cornelia, Sanchez-Juan, P, Bishop, MT, Kovacs, GG, Calero, M, Aulchenko, YS, Ladogana, A, Boyd, A, Lewis, V, Ponto, C, Calero, O, Poleggi, A, Carracedo, A, van der Lee, Sven, Strobel, T, Rivadeneira, Fernando, Hofman, Bert, Haik, S, Combarros, O, Berciano, J, Uitterlinden, André, Collins, SJ, Budka, H, Brandel, JP, Laplanche, JL, Pocchiari, M, Zerr, I, Knight, RSG, Will, RG, and Duijn, Cornelia

Abstract

We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10(-9)) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10(-8)) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10(-8)) and rs6951643 (p-value=3.91x10(-5)) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top 100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis.

Published
2015

58. Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease

Author

Bullock, JM, Medway, C, Cortina-Borja, M, Turton, JC, Prince, JA, Ibrahim-Verbaas, CA, Schuur, M, Breteler, MM, van Duijn, CM, Kehoe, PG, Barber, R, Coto, E, Alvarez, V, Deloukas, P, Hammond, N, Combarros, O, Mateo, I, Warden, DR, Lehmann, MG, Belbin, O, Brown, K, Wilcock, GK, Heun, R, Kölsch, H, Smith, AD, Lehmann, DJ, Morgan, K, Neurology, and Epidemiology

Subjects
Apolipoprotein E, Genetic Markers, Male, Aging, Kinesins, Genome-wide association study, Locus (genetics), IDE locus, Biology, Bioinformatics, Insulysin, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Alzheimer Disease, Risk Factors, Prevalence, Humans, Genetic Predisposition to Disease, Genetic Testing, Allele, Alzheimer's risk, 030304 developmental biology, Aged, Glutathione Transferase, Genetics, Aged, 80 and over, Homeodomain Proteins, 0303 health sciences, General Neuroscience, Chromosome Mapping, Epistasis, Genetic, Odds ratio, Heritability, Europe, Genetic Loci, Epistasis, GSTM3, Female, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology, Transcription Factors
Abstract

Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the epsilon 4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p >= 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the epsilon 4 allele of apolipoprotein E genotype, and geographic region. (C) 2013 Elsevier Inc. All rights reserved.

Published
2012

59. Interaction of insulin and PPAR-α genes in Alzheimer's disease: the Epistasis Project

Author

Kölsch, H, Lehmann, DJ, Ibrahim-Verbaas, CA, Combarros, O, Van Duijn, CM, Hammond, N, Belbin, O, Cortina-Borja, M, Lehmann, MG, Aulchenko, YS, Schuur, M, Breteler, M, Wilcock, GK, Brown, K, Kehoe, PG, Barber, R, Coto, E, Alvarez, V, Deloukas, P, Mateo, I, Maier, W, Morgan, K, Warden, DR, Smith, AD, Heun, R, Neurology, and Epidemiology

Subjects
Male, Genotype, medicine.medical_treatment, Apolipoprotein E4, Peroxisome proliferator-activated receptor, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Gene Frequency, Polymorphism (computer science), Alzheimer Disease, medicine, Humans, Insulin, Genetic Predisposition to Disease, PPAR alpha, Allele frequency, Biological Psychiatry, Genetic Association Studies, Aged, chemistry.chemical_classification, Genetics, Aged, 80 and over, Intron, Epistasis, Genetic, Europe, Psychiatry and Mental health, Neurology, chemistry, Female, Neurology (clinical), Peroxisome proliferator-activated receptor alpha
Abstract

We are most grateful to the Moulton Charitable Foundation for a grant to fund the Epistasis Project, to all those who have provided support for the individual clinical studies and to the Alzheimer’s Research Trust. GKW was partly funded by the NIHR Biomedical Research Centre Programme, Oxford., Kölsch, H., Lehmann, D.J., Ibrahim-Verbaas, C.A., Combarros, O., Van Duijn, C.M., Hammond, N., Belbin, O., Cortina-Borja, M., Lehmann, M.G., Aulchenko, Y.S., Schuur, M., Breteler, M., Wilcock, G.K., Brown, K., Kehoe, P.G., Barber, R., Coto, E., Alvarez, V., Deloukas, P., Mateo, I., Maier, W., Morgan, K., Warden, D.R., Smith, A.D., Heun, R.

Published
2012

60. Interactions between PPAR-α and inflammation-related cytokine genes on the development of Alzheimer's disease, observed by the Epistasis project

Author

Heun, R, Kölsch, H, Ibrahim-Verbaas, CA, Combarros, O, Aulchenko, YS, Breteler, M, Schuur, M, van Duijn, CM, Hammond, N, Belbin, O, Cortina-Borja, M, Wilcock, GK, Brown, K, Barber, R, Kehoe, PG, Coto, E, Alvarez, V, Lehmann, MG, Deloukas, P, Mateo, I, Morgan, K, Warden, DR, Smith, AD, and Lehmann, DJ

Abstract

Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer's disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-α, interleukins (IL) IL1α, IL-1β, IL-6, and IL-10 may interact to increase AD risk. Methods: The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein ε4 allele (APOEε4). Adjusted synergy factors were derived from interaction terms (p

Published
2012

61. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer’s disease

Author

Lambert, J. C., Grenier-Boley, B., Harold, D., Zelenika, D., Chouraki, V., Kamatani, Y., Sleegers, K., Ikram, M.A., Hiltunen, M., Reitz, Christiane, Mateo, I., Feulner, T., Bullido, M., Galimberti, D., Concari, L., Alvarez, V., Sims, R., Gerrish, A., Chapman, J., Deniz-Naranjo, C., Solfrizzi, V., Sorbi, S., Arosio, B., Spalletta, G., Siciliano, G., Epelbaum, J., Hannequin, D., Dartigues, J. F., Tzourio, C., Berr, C., Schrijvers, E. M. C., Rogers, R., Tosto, Giuseppe, Pasquier, F., Bettens, K., Van Cauwenberghe, C., Fratiglioni, L., Graff, C., Delepine, M., Ferri, R., Reynolds, C. A., Lannfelt, L., Ingelsson, M., Prince, J. A., Pilotto, A., Chillotti, C., Seripa, D., Boland, A., Mancuso, M., Bossu, P., Annoni, G., Nacmias, B., Bosco, P., Panza, F., Sanchez-Garcia, F., Del Zompo, M., Coto, E., Owen, M., Valdivieso, F., O'Donovan, M., Caffara, P., Scarpini, E., Campion, D., Buee, L., Combarros, O., Soininen, H., Breteler, M., Riemenschneider, M., Van Broeckhoven, C., Alperovitch, A., Williams, J., Lathrop, M., Tregouet, D. A., Amouyel, P., EADI Consortium, and GERAD Consortium

Subjects
Molecular biology, FOS: Biological sciences, Genetics, Psychobiology
Abstract

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case–control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P=1.1 × 10−10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10−7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Published
2012
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62. Interactions between PPAR-alpha and inflammation-related cytokine genes on the development of Alzheimer's disease, observed by the Epitasis Project

Author

Heun, R, Kölsch, H, Verbaas, Carla, Combarros, O, Aulchenko, YS, Breteler, Monique, Schuur, Maaike, Duijn, Cornelia, Hammond, N, Belbin, O, Cortina-Borja, M, Wilcock, GK, Brown, K, Barber, R, Kehoe, PG, Coto, E, Alvarez, V, Lehmann, MG, Deloukas, P, Mateo, I, Morgan, K, Warden, DR, Smith, AD, Lehmann, DJ, Neurology, and Epidemiology

Published
2012

63. Genetic variation in APOE cluster region and Alzheimer's disease risk

Author

Cervantes, S, Samaranch, L, Vidal-Taboada, JM, Lamet, I, Bullido, MJ, Frank-Garcia, A, Coria, F, Lleo, A, Clarimon, J, Lorenzo, E, Alonso, E, Sanchez-Juan, P, Rodriguez-Rodriguez, E, Combarros, O, Rosichi, M, Vilella, E, and Pastor, P

Subjects
APOC2, APOC1, Mapping, Genetics, Mild cognitive impairment, TOMM40, Alzheimer's disease, APOE, APOC4
Abstract

We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimer's disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE epsilon 4. Rs5158 (APOC4 intron 1) and rs10413089 (3' to APOC2) showed a trend toward an increase in AD risk independently from APOE epsilon 4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk. (C) 2011 Elsevier Inc. All rights reserved.

Published
2011

64. The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study

Author

Lambert, J., Sleegers, K., Gonzalez-Perez, A., Ingelsson, M., Beecham, G., Hiltunen, M., Combarros, O., Bullido, M., Brouwers, N., Bettens, K., Berr, C., Pasquier, F., Richard, F., Dekosky, S., Hannequin, D., Haines, J., Tognoni, G., Fievet, N., Dartigues, J., Tzourio, C., Engelborghs, S., Arosio, B., Coto, E., De Deyn, P., Del Zompo, M., Mateo, I., Boada, M., Antunez, C., Lopez-Arrieta, J., Epelbaum, J., Schjeide, B., Frank-Garcia, A., Giedraitis, V., Helisalmi, S., Porcellini, E., Pilotto, A., Forti, P., Ferri, R., Delepine, M., Zelenika, D., Lathrop, M., Scarpini, E., Siciliano, G., Solfrizzi, V., Sorbi, S., Spalletta, G., Ravaglia, G., Valdivieso, F., Vepsalainen, S., Alvarez, V., Bosco, P., Mancuso, M., Panza, F., Nacmias, B., Bossu, P., Hanon, O., Piccardi, P., Annoni, G., Mann, D., Marambaud, P., Seripa, D., Galimberti, D., Tanzi, R., Bertram, L., Lendon, C., Lannfelt, L., Licastro, F., Campion, D., Pericak-Vance, M., Soininen, H., Van Broeckhoven, C., Alperovitch, A., Ruiz, A., Kamboh, M., and Amouyel, P.

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the epsilon4 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 epsilon4 allele of the APOE gene.

Published
2010

65. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Author

Escott-Price, V. (Valentina), Bellenguez, C. (Céline), Wang, L.S. (Li-San), Choi, S.-H. (Seung-Hoan), Harold, D. (Denise), Jones, L. (Louisa), Holmans, P.A. (Peter), Gerrish, A. (Amy), Vedernikov, A. (Alexey), Richards, A. (Alex), DeStefano, A.L. (Anita), Lambert, J.-C. (J.), Ibrahim-Verbaas, C.A. (Carla), Naj, A.C. (Adam), Sims, R. (Rebecca), Jun, Y. (Yang), Bis, J.C. (Joshua), Beecham, G.W. (Gary), Grenier-Boley, B. (Benjamin), Russo, G. (Giancarlo), Thornton-Wells, T.A. (Tricia), Denning, N. (Nicola), Smith, A.V. (Davey), Chouraki, V. (Vincent), Thomas, C. (Charlene), Ikram, M.A. (Arfan), Zelenika, D. (Diana), Vardarajan, B.N. (Badri), Kamatani, Y. (Yoichiro), Lin, C.-F. (Chiao-Feng), Schmidt, R. (Reinhold), Kunkle, B. (Brian), Dunstan, M.L. (Melanie), Vronskaya, M. (Maria), Johnson, A.D. (Andrew), Ruiz, A. (Agustin), Bihoreau, M.-T. (Marie-Thérèse), Reitz, C. (Christiane), Pasquier, F. (Florence), Hollingworth, P. (Paul), Hanon, O. (Olivier), Fitzpatrick, A.L. (Annette), Buxbaum, J.D. (Joseph D), Campion, D. (Dominique), Crane, L.M.A., Becker, C.B.T. (Clinton), Gudnason, V. (Vilmundur), Cruchaga, C. (Carlos), Craig, D. (David), Amin, N. (Najaf), Berr, C. (Claudine), Lopez, O.L. (Oscar), Jager, P.L. (Philip) de, Deramecourt, V. (Vincent), Johnston, J.A. (Janet), Evans, D.A. (Denis), Lovestone, S. (Simon), Letenneur, L., Hernández, I. (Isabel), Rubinsztein, D.C. (David), Eiriksdottir, G. (Gudny), Sleegers, K. (Kristel), Goate, A.M. (Alison), Fiévet, N. (Nathalie), Huentelman, M.J. (Matthew), Gill, M. (Michael), Brown, K. (Kristelle), Kamboh, M.I. (M. Ilyas), Keller, L. (Lina), Barberger-Gateau, P. (Pascale), McGuinness, B. (Bernadette), Larson, E.B. (Eric), Myers, A.J. (Amanda), Dufouil, C. (Carole), Todd, S. (Stephen), Wallon, D. (David), Love, S. (Seth), Rogaeva, E. (Ekaterina), Gallacher, J. (John), St George-Hyslop, P.H. (Peter), Clarimon, J. (Jordi), Lleo, A. (Alberto), Bayer, T. (T.), Tsuang, D.W. (Debby), Yu, L. (Lei), Tsolaki, M. (Magda), Bossù, P. (Paola), Spalletta, G. (Gianfranco), Proitsi, P. (Petroula), Collinge, J. (John), Sorbi, S. (Sandro), Sanchez Garcia, F. (Florentino), Fox, N.C. (Nick), Hardy, J. (John), Naranjo, A. (Antonio), Bosco, P. (Paolo), Clarke, R. (Robert), Brayne, C. (Carol), Galimberti, D. (Daniela), Scarpini, E. (Elio), Bonuccelli, U. (Ubaldo), Mancuso, M. (Michelangelo), Siciliano, G. (Gabriele), Moebus, S. (Susanne), Mecocci, P. (Patrizia), Zompo, M.D. (Maria) del, Maier, W. (Wolfgang), Hampel, H. (Harald), Pilotto, A. (Alberto), Frank-Garcia, A. (Ana), Panza, F. (Francesco), Solfrizzi, V. (Vincenzo), Caffarra, P. (Paolo), Nacmias, B. (Benedetta), Perry, W. (William), Mayhaus, M. (Manuel), Lannfelt, L. (Lars), Hakonarson, H. (Hakon), Pichler, I. (Irene), Carrasquillo, M.M. (Minerva), Ingelsson, M. (Martin), Beekly, D. (Duane), Alvarez, V. (Victoria), Zou, F. (Fanggeng), Valladares, O. (Otto), Younkin, S., Coto, E. (Eliecer), Hamilton-Nelson, K.L. (Kara), Gu, W. (Wei), Razquin, C. (Cristina), Pastor, P. (Pau), Mateo, I. (Ignacio), Owen, M.J. (Michael), Faber, K.M. (Kelley), Jonsson, P.V. (Palmi), Combarros, O. (Onofre), O'Donovan, M. (Michael), Cantwell, L.B. (Laura), Soininen, H. (Hilkka), Blacker, D. (Deborah), Mead, S. (Simon), Mosley, T.H. (Thomas), Bennett, D.A. (David), Harris, T.B. (Tamara), Fratiglioni, L. (Laura), Holmes, C. (Clive), Bruijn, R.F.A.G. (Renée) de, Passmore, P.A. (Peter), Montine, T.J. (Thomas), Bettens, K. (Karolien), Rotter, J.I. (Jerome), Brice, A., Morgan, K. (Kevin), Foroud, T. (Tatiana), Kukull, W.A., Hannequin, D. (Didier), Powell, J. (John), Nalls, M.A. (Michael), Ritchie, K. (Karen), Lunetta, K.L. (Kathryn), Kauwe, J.S.K. (John), Boerwinkle, E.A. (Eric), Riemenschneider, M. (Matthias), Boada, M. (Mercè), Hiltunen, M. (Mikko), Martin, E.R. (Eden), Rujescu, D. (Dan), Dartigues, J.-F., Mayeux, R. (Richard), Tzourio, C. (Christophe), Hofman, A. (Albert), Nöthen, M.M. (Markus), Graff, M.J. (Maud J.L.), Psaty, B.M. (Bruce), Haines, J.L. (Jonathan), Lathrop, M. (Mark), Pericak-Vance, M.A. (Margaret), Launer, L.J. (Lenore), Broeckhoven, C. (Christine) van, Farrer, L.A. (Lindsay), Duijn, C.M. (Cornelia) van, Ramirez, A. (Alfredo), Seshadri, S. (Sudha), Schellenberg, G.D. (Gerard), Amouyel, P. (Philippe), Williams, J. (Julie), Escott-Price, V. (Valentina), Bellenguez, C. (Céline), Wang, L.S. (Li-San), Choi, S.-H. (Seung-Hoan), Harold, D. (Denise), Jones, L. (Louisa), Holmans, P.A. (Peter), Gerrish, A. (Amy), Vedernikov, A. (Alexey), Richards, A. (Alex), DeStefano, A.L. (Anita), Lambert, J.-C. (J.), Ibrahim-Verbaas, C.A. (Carla), Naj, A.C. (Adam), Sims, R. (Rebecca), Jun, Y. (Yang), Bis, J.C. (Joshua), Beecham, G.W. (Gary), Grenier-Boley, B. (Benjamin), Russo, G. (Giancarlo), Thornton-Wells, T.A. (Tricia), Denning, N. (Nicola), Smith, A.V. (Davey), Chouraki, V. (Vincent), Thomas, C. (Charlene), Ikram, M.A. (Arfan), Zelenika, D. (Diana), Vardarajan, B.N. (Badri), Kamatani, Y. (Yoichiro), Lin, C.-F. (Chiao-Feng), Schmidt, R. (Reinhold), Kunkle, B. (Brian), Dunstan, M.L. (Melanie), Vronskaya, M. (Maria), Johnson, A.D. (Andrew), Ruiz, A. (Agustin), Bihoreau, M.-T. (Marie-Thérèse), Reitz, C. (Christiane), Pasquier, F. (Florence), Hollingworth, P. (Paul), Hanon, O. (Olivier), Fitzpatrick, A.L. (Annette), Buxbaum, J.D. (Joseph D), Campion, D. (Dominique), Crane, L.M.A., Becker, C.B.T. (Clinton), Gudnason, V. (Vilmundur), Cruchaga, C. (Carlos), Craig, D. (David), Amin, N. (Najaf), Berr, C. (Claudine), Lopez, O.L. (Oscar), Jager, P.L. (Philip) de, Deramecourt, V. (Vincent), Johnston, J.A. (Janet), Evans, D.A. (Denis), Lovestone, S. (Simon), Letenneur, L., Hernández, I. (Isabel), Rubinsztein, D.C. (David), Eiriksdottir, G. (Gudny), Sleegers, K. (Kristel), Goate, A.M. (Alison), Fiévet, N. (Nathalie), Huentelman, M.J. (Matthew), Gill, M. (Michael), Brown, K. (Kristelle), Kamboh, M.I. (M. Ilyas), Keller, L. (Lina), Barberger-Gateau, P. (Pascale), McGuinness, B. (Bernadette), Larson, E.B. (Eric), Myers, A.J. (Amanda), Dufouil, C. (Carole), Todd, S. (Stephen), Wallon, D. (David), Love, S. (Seth), Rogaeva, E. (Ekaterina), Gallacher, J. (John), St George-Hyslop, P.H. (Peter), Clarimon, J. (Jordi), Lleo, A. (Alberto), Bayer, T. (T.), Tsuang, D.W. (Debby), Yu, L. (Lei), Tsolaki, M. (Magda), Bossù, P. (Paola), Spalletta, G. (Gianfranco), Proitsi, P. (Petroula), Collinge, J. (John), Sorbi, S. (Sandro), Sanchez Garcia, F. (Florentino), Fox, N.C. (Nick), Hardy, J. (John), Naranjo, A. (Antonio), Bosco, P. (Paolo), Clarke, R. (Robert), Brayne, C. (Carol), Galimberti, D. (Daniela), Scarpini, E. (Elio), Bonuccelli, U. (Ubaldo), Mancuso, M. (Michelangelo), Siciliano, G. (Gabriele), Moebus, S. (Susanne), Mecocci, P. (Patrizia), Zompo, M.D. (Maria) del, Maier, W. (Wolfgang), Hampel, H. (Harald), Pilotto, A. (Alberto), Frank-Garcia, A. (Ana), Panza, F. (Francesco), Solfrizzi, V. (Vincenzo), Caffarra, P. (Paolo), Nacmias, B. (Benedetta), Perry, W. (William), Mayhaus, M. (Manuel), Lannfelt, L. (Lars), Hakonarson, H. (Hakon), Pichler, I. (Irene), Carrasquillo, M.M. (Minerva), Ingelsson, M. (Martin), Beekly, D. (Duane), Alvarez, V. (Victoria), Zou, F. (Fanggeng), Valladares, O. (Otto), Younkin, S., Coto, E. (Eliecer), Hamilton-Nelson, K.L. (Kara), Gu, W. (Wei), Razquin, C. (Cristina), Pastor, P. (Pau), Mateo, I. (Ignacio), Owen, M.J. (Michael), Faber, K.M. (Kelley), Jonsson, P.V. (Palmi), Combarros, O. (Onofre), O'Donovan, M. (Michael), Cantwell, L.B. (Laura), Soininen, H. (Hilkka), Blacker, D. (Deborah), Mead, S. (Simon), Mosley, T.H. (Thomas), Bennett, D.A. (David), Harris, T.B. (Tamara), Fratiglioni, L. (Laura), Holmes, C. (Clive), Bruijn, R.F.A.G. (Renée) de, Passmore, P.A. (Peter), Montine, T.J. (Thomas), Bettens, K. (Karolien), Rotter, J.I. (Jerome), Brice, A., Morgan, K. (Kevin), Foroud, T. (Tatiana), Kukull, W.A., Hannequin, D. (Didier), Powell, J. (John), Nalls, M.A. (Michael), Ritchie, K. (Karen), Lunetta, K.L. (Kathryn), Kauwe, J.S.K. (John), Boerwinkle, E.A. (Eric), Riemenschneider, M. (Matthias), Boada, M. (Mercè), Hiltunen, M. (Mikko), Martin, E.R. (Eden), Rujescu, D. (Dan), Dartigues, J.-F., Mayeux, R. (Richard), Tzourio, C. (Christophe), Hofman, A. (Albert), Nöthen, M.M. (Markus), Graff, M.J. (Maud J.L.), Psaty, B.M. (Bruce), Haines, J.L. (Jonathan), Lathrop, M. (Mark), Pericak-Vance, M.A. (Margaret), Launer, L.J. (Lenore), Broeckhoven, C. (Christine) van, Farrer, L.A. (Lindsay), Duijn, C.M. (Cornelia) van, Ramirez, A. (Alfredo), Seshadri, S. (Sudha), Schellenberg, G.D. (Gerard), Amouyel, P. (Philippe), and Williams, J. (Julie)

Published
2014
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66. Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease

Author

Escott-Price, V, Bellenguez, C, Wang, LS (Li-San), Choi, SH, Harold, D, Jones, L, Holmans, P, Gerrish, A, Vedernikov, A, Richards, A, DeStefano, AL, Lambert, JC, Verbaas, Carla, Naj, AC, Sims, R, Jun, G, Bis, JC, Beecham, GW, Grenier-Boley, B, Russo, G, Thornton-Wells, TA, Denning, N, Smith, AV, Chouraki, V, Thomas, C, Ikram, Arfan, Zelenika, D, Vardarajan, BN, Kamatani, Y, Lin, CF, Schmidt, Heléna, Kunkle, B, Dunstan, ML, Vronskaya, M, Johnson, AD, Ruiz, A, Bihoreau, MT, Reitz, C, Pasquier, F, Hollingworth, P, Hanon, O, Fitzpatrick, AL, Buxbaum, JD, Campion, D, Crane, PK, Baldwin, C, Becker, T, Gudnason, V, Cruchaga, C, Craig, D, Amin, Najaf, Berr, C, Lopez, OL, De Jager, PL, Deramecourt, V, Johnston, JA, Evans, D, Lovestone, S, Letenneur, L, Hernandez, I, Rubinsztein, DC, Eiriksdottir, G, Sleegers, K (Kristel), Goate, AM, Fievet, N, Huentelman, MJ, Gill, M, Brown, K, Kamboh, MI, Keller, L, Barberger-Gateau, P, McGuinness, B, Larson, EB, Myers, AJ, Dufouil, C, Todd, S, Wallon, D, Love, S, Rogaeva, E, Gallacher, J, St George-Hyslop, P, Clarimon, J, Lleo, A, Bayer, A, Tsuang, DW, Yu, L, Tsolaki, M, Bossu, P, Spalletta, G, Proitsi, P, Collinge, J, Sorbi, S, Garcia, FS, Fox, NC, Hardy, J, Naranjo, MCD, Bosco, P, Clarke, R, Brayne, C, Galimberti, D, Scarpini, E, Bonuccelli, U, Mancuso, M, Siciliano, G, Moebus, S, Mecocci, P, Del Zompo, M, Maier, W, Hampel, H, Pilotto, A, Frank-Garcia, A, Panza, F, Solfrizzi, V, Caffarra, P, Nacmias, B, Perry, W, Mayhaus, M, Lannfelt, L, Hakonarson, H, Pichler, S, Carrasquillo, MM, Ingelsson, M, Beekly, D, Alvarez, V, Zou, FG, Valladares, O, Younkin, SG, Coto, E, Hamilton-Nelson, KL, Gu, W, Razquin, C, Pastor, P, Mateo, I, Owen, MJ, Faber, KM, Jonsson, PV, Combarros, O, O'Donovan, MC, Cantwell, LB, Soininen, H, Blacker, D, Mead, S, Mosley, TH, Bennett, DA, Harris, TB, Fratiglioni, L, Holmes, C, Bruijn, Renee, Passmore, P, Montine, TJ, Bettens, K, Rotter, JI, Brice, A, Morgan, K, Foroud, TM, Kukull, WA, Hannequin, D, Powell, JF, Nalls, MA, Ritchie, K, Lunetta, KL, Kauwe, JSK, Boerwinkle, E, Riemenschneider, M, Boada, M, Hiltunen, M, Martin, ER, Schmidt, R, Rujescu, D, Dartigues, JF, Mayeux, R, Tzourio, C, Hofman, Bert, Nothen, MM, Graff, C, Psaty, BM, Haines, JL, Lathrop, M, Pericak-Vance, MA, Launer, LJ (Lenore), van Broeckhoven, C, Farrer, LA, Duijn, Cornelia, Ramirez, A, Seshadri, S, Schellenberg, GD, Amouyel, P, Williams, J, Escott-Price, V, Bellenguez, C, Wang, LS (Li-San), Choi, SH, Harold, D, Jones, L, Holmans, P, Gerrish, A, Vedernikov, A, Richards, A, DeStefano, AL, Lambert, JC, Verbaas, Carla, Naj, AC, Sims, R, Jun, G, Bis, JC, Beecham, GW, Grenier-Boley, B, Russo, G, Thornton-Wells, TA, Denning, N, Smith, AV, Chouraki, V, Thomas, C, Ikram, Arfan, Zelenika, D, Vardarajan, BN, Kamatani, Y, Lin, CF, Schmidt, Heléna, Kunkle, B, Dunstan, ML, Vronskaya, M, Johnson, AD, Ruiz, A, Bihoreau, MT, Reitz, C, Pasquier, F, Hollingworth, P, Hanon, O, Fitzpatrick, AL, Buxbaum, JD, Campion, D, Crane, PK, Baldwin, C, Becker, T, Gudnason, V, Cruchaga, C, Craig, D, Amin, Najaf, Berr, C, Lopez, OL, De Jager, PL, Deramecourt, V, Johnston, JA, Evans, D, Lovestone, S, Letenneur, L, Hernandez, I, Rubinsztein, DC, Eiriksdottir, G, Sleegers, K (Kristel), Goate, AM, Fievet, N, Huentelman, MJ, Gill, M, Brown, K, Kamboh, MI, Keller, L, Barberger-Gateau, P, McGuinness, B, Larson, EB, Myers, AJ, Dufouil, C, Todd, S, Wallon, D, Love, S, Rogaeva, E, Gallacher, J, St George-Hyslop, P, Clarimon, J, Lleo, A, Bayer, A, Tsuang, DW, Yu, L, Tsolaki, M, Bossu, P, Spalletta, G, Proitsi, P, Collinge, J, Sorbi, S, Garcia, FS, Fox, NC, Hardy, J, Naranjo, MCD, Bosco, P, Clarke, R, Brayne, C, Galimberti, D, Scarpini, E, Bonuccelli, U, Mancuso, M, Siciliano, G, Moebus, S, Mecocci, P, Del Zompo, M, Maier, W, Hampel, H, Pilotto, A, Frank-Garcia, A, Panza, F, Solfrizzi, V, Caffarra, P, Nacmias, B, Perry, W, Mayhaus, M, Lannfelt, L, Hakonarson, H, Pichler, S, Carrasquillo, MM, Ingelsson, M, Beekly, D, Alvarez, V, Zou, FG, Valladares, O, Younkin, SG, Coto, E, Hamilton-Nelson, KL, Gu, W, Razquin, C, Pastor, P, Mateo, I, Owen, MJ, Faber, KM, Jonsson, PV, Combarros, O, O'Donovan, MC, Cantwell, LB, Soininen, H, Blacker, D, Mead, S, Mosley, TH, Bennett, DA, Harris, TB, Fratiglioni, L, Holmes, C, Bruijn, Renee, Passmore, P, Montine, TJ, Bettens, K, Rotter, JI, Brice, A, Morgan, K, Foroud, TM, Kukull, WA, Hannequin, D, Powell, JF, Nalls, MA, Ritchie, K, Lunetta, KL, Kauwe, JSK, Boerwinkle, E, Riemenschneider, M, Boada, M, Hiltunen, M, Martin, ER, Schmidt, R, Rujescu, D, Dartigues, JF, Mayeux, R, Tzourio, C, Hofman, Bert, Nothen, MM, Graff, C, Psaty, BM, Haines, JL, Lathrop, M, Pericak-Vance, MA, Launer, LJ (Lenore), van Broeckhoven, C, Farrer, LA, Duijn, Cornelia, Ramirez, A, Seshadri, S, Schellenberg, GD, Amouyel, P, and Williams, J

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 = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) 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.

Published
2014

68. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease

Author

Lambert, Jc, Heath, S, Even, G, Campion, D, Sleegers, K, Hiltunen, M, Combarros, O, Zelenika, D, Bullido, Mj, Tavernier, B, Letenneur, L, Bettens, K, Berr, C, Pasquier, F, Fiévet, N, BARBERGER GATEAU, P, Engelborghs, S, DE DEYN, P, Mateo, I, Franck, A, Helisalmi, S, Porcellini, E, Hanon, O, Siciliano, Gabriele, DE PANCORBO MM, Lendon, C, Dufouil, C, Jaillard, C, Leveillard, T, Alvarez, V, Bosco, P, Mancuso, Michelangelo, Panza, F, Nacmias, B, Bossù, P, Piccardi, P, Annoni, G, Seripa, D, Galimberti, D, Hannequin, D, Licastro, F, Soininen, H, Ritchie, K, Blanché, H, Dartigues, Jf, Tzourio, C, Gut, I, VAN BROECKHOVEN, C, Alpérovitch, A, Lathrop, M, and Amouyel, P.

Published
2009

69. Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease

Author

Bullock, J.M. (James), Medway, C. (Christopher), Cortina-Borja, M. (Mario), Turton, J.C. (James), Prince, J.A. (Jonathan), Ibrahim-Verbaas, C.A. (Carla), Schuur, M. (Maaike), Breteler, M.M.B. (Monique), Duijn, C.M. (Cornelia) van, Kehoe, P.G. (Patrick), Barber, R. (Rachel), Coto, E. (Eliecer), Alvarez, V. (Victoria), Deloukas, P. (Panagiotis), Hammond, N. (Naomi), Combarros, O. (Onofre), Mateo, I. (Ignacio), Warden, D.R. (Donald), Lehmann, M.G. (Michael), Belbin, O. (Olivia), Brown, K. (Kristelle), Wilcock, G.K. (Gordon), Heun, R. (Reinhard), Kölsch, H. (Heike), Smith, A.D., Lehmann, D.J. (Donald), Morgan, K. (Kevin), Bullock, J.M. (James), Medway, C. (Christopher), Cortina-Borja, M. (Mario), Turton, J.C. (James), Prince, J.A. (Jonathan), Ibrahim-Verbaas, C.A. (Carla), Schuur, M. (Maaike), Breteler, M.M.B. (Monique), Duijn, C.M. (Cornelia) van, Kehoe, P.G. (Patrick), Barber, R. (Rachel), Coto, E. (Eliecer), Alvarez, V. (Victoria), Deloukas, P. (Panagiotis), Hammond, N. (Naomi), Combarros, O. (Onofre), Mateo, I. (Ignacio), Warden, D.R. (Donald), Lehmann, M.G. (Michael), Belbin, O. (Olivia), Brown, K. (Kristelle), Wilcock, G.K. (Gordon), Heun, R. (Reinhard), Kölsch, H. (Heike), Smith, A.D., Lehmann, D.J. (Donald), and Morgan, K. (Kevin)

Abstract

Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial " hidden heritability." It is thought that some of this missing heritability may be beca

Published
2013
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70. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Author

Lambert, JC, Grenier-Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K (Kristel), Ikram, Arfan, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz-Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, JF, Tzourio, C, Berr, C, Schrijvers, Elisabeth, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, CA, Lannfelt, L, Ingelsson, M, Prince, JA, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossu, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez-Garcia, F, Del Zompo, M, Coto, E, Owen, M, O'Donovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buee, L, Campion, D, Soininen, H, Breteler, Monique, Riemenschneider, M, van Broeckhoven, C, Alperovitch, A, Lathrop, M, Tregouet, DA, Williams, J, Amouyel, P, Lambert, JC, Grenier-Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K (Kristel), Ikram, Arfan, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz-Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, JF, Tzourio, C, Berr, C, Schrijvers, Elisabeth, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, CA, Lannfelt, L, Ingelsson, M, Prince, JA, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossu, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez-Garcia, F, Del Zompo, M, Coto, E, Owen, M, O'Donovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buee, L, Campion, D, Soininen, H, Breteler, Monique, Riemenschneider, M, van Broeckhoven, C, Alperovitch, A, Lathrop, M, Tregouet, DA, Williams, J, and Amouyel, P

Published
2013

71. Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease

Author

Bullock, JM, Medway, C, Cortina-Borja, M, Turton, JC, Prince, JA, Verbaas, Carla, Schuur, Maaike, Breteler, Monique, Duijn, Cornelia, Kehoe, PG, Barber, R, Coto, E, Alvarez, V, Deloukas, P, Hammond, N, Combarros, O, Mateo, I, Warden, DR, Lehmann, MG, Belbin, O, Brown, K, Wilcock, GK, Heun, R, Kolsch, H, Smith, AD, Lehmann, DJ, Morgan, K, Bullock, JM, Medway, C, Cortina-Borja, M, Turton, JC, Prince, JA, Verbaas, Carla, Schuur, Maaike, Breteler, Monique, Duijn, Cornelia, Kehoe, PG, Barber, R, Coto, E, Alvarez, V, Deloukas, P, Hammond, N, Combarros, O, Mateo, I, Warden, DR, Lehmann, MG, Belbin, O, Brown, K, Wilcock, GK, Heun, R, Kolsch, H, Smith, AD, Lehmann, DJ, and Morgan, K

Published
2013

72. [Hereditary ataxias and paraplegias: a clinicogenetic review]

Author

Berciano J, Jon Infante, Mateo I, and Combarros O

Subjects
Paraplegia, Humans, Ataxia
Abstract

Hereditary ataxias encompass a series of syndromes basically characterised by progressive cerebellar ataxia of slow clinical course (occasionally, periodic ataxia or spastic paraparesis) and primary spinocerebellar degeneration. The prevalence ratio of these syndromes in Spain is 20 cases per 100,000 inhabitants. Initially the ataxias were classified on the basis of clinicopathological criteria. Starting from the seminal papers by Harding published 20 years ago, a clinicogenetic classification was introduced that has given way to the present molecular classification. There have been localised about forty loci. In dominant ataxias the most frequent molecular defect is a dynamic CAG expansion responsible for abnormal polyglutamine tract transcription. The identification of such molecular defect has made it possible detection of gene carriers in clinical practice, this involving both presymptomatic and prenatal diagnosis; moreover, such molecular discoveries have contributed to develop a new pathogenetic era. A homozygous and intronic GAA expansion is the molecular basis of Friedreich's ataxia. This finding has also made it possible a molecular diagnosis in clinical practice. Molecular studies have demonstrated that hereditary spastic paraplegia is another heterogeneous genetic disorder.

Published
2002

73. Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project.

Author

Lehmann, D.J., Schuur, M., Warden, D.R., Hammond, N., Belbin, O., Kolsch, H., Lehmann, M.G., Wilcock, G.K., Brown, K., Kehoe, P.G., Morris, C.M., Barker, R., Coto, E., Alvarez, V., Deloukas, P., Mateo, I., Gwilliam, R., Combarros, O., Arias Vasquez, A., Aulchenko, Y.S., Ikram, M.A., Breteler, M.M.B., Duijn, C.M. van, Oulhaj, A., Heun, R., Cortina-Borja, M., Morgan, K., Robson, K., Smith, A.D., Lehmann, D.J., Schuur, M., Warden, D.R., Hammond, N., Belbin, O., Kolsch, H., Lehmann, M.G., Wilcock, G.K., Brown, K., Kehoe, P.G., Morris, C.M., Barker, R., Coto, E., Alvarez, V., Deloukas, P., Mateo, I., Gwilliam, R., Combarros, O., Arias Vasquez, A., Aulchenko, Y.S., Ikram, M.A., Breteler, M.M.B., Duijn, C.M. van, Oulhaj, A., Heun, R., Cortina-Borja, M., Morgan, K., Robson, K., and Smith, A.D.

Abstract

1 januari 2012, Item does not contain fulltext, Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9; 0.007) in subjects with the APOEepsilon4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases.

Published
2012

74. Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations

Author

Lambert, J, Zelenika, D, Hiltunen, M, Chouraki, V, Combarros, O, Bullido, M, Tognoni, G, Fiévet, N, Boland, A, Arosio, B, Coto, E, Zompo, M, Mateo, I, Frank Garcia, A, Helisalmi, S, Porcellini, E, Pilotto, A, Forti, P, Ferri, R, Delepine, M, Scarpini, E, Siciliano, G, Solfrizzi, V, Sorbi, S, Spalletta, G, Ravaglia, G, Valdivieso, F, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Piccardi, P, Annoni, G, Seripa, D, Galimberti, D, Licastro, F, Lathrop, M, Soininen, H, Amouyel, P, Bullido, MJ, Zompo, MD, ANNONI, GIORGIO, Amouyel, P., Lambert, J, Zelenika, D, Hiltunen, M, Chouraki, V, Combarros, O, Bullido, M, Tognoni, G, Fiévet, N, Boland, A, Arosio, B, Coto, E, Zompo, M, Mateo, I, Frank Garcia, A, Helisalmi, S, Porcellini, E, Pilotto, A, Forti, P, Ferri, R, Delepine, M, Scarpini, E, Siciliano, G, Solfrizzi, V, Sorbi, S, Spalletta, G, Ravaglia, G, Valdivieso, F, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Piccardi, P, Annoni, G, Seripa, D, Galimberti, D, Licastro, F, Lathrop, M, Soininen, H, Amouyel, P, Bullido, MJ, Zompo, MD, ANNONI, GIORGIO, and Amouyel, P.

Abstract

Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10-7, and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10-7, respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10-3). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation. © 2011 Elsevier Inc.

Published
2011

75. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

Author

Hollingworth, P, Harold, D, Sims, R, Gerrish, A, Lambert, J, Carrasquillo, M, Abraham, R, Hamshere, M, Pahwa, J, Moskvina, V, Dowzell, K, Jones, N, Stretton, A, Thomas, C, Richards, A, Ivanov, D, Widdowson, C, Chapman, J, Lovestone, S, Powell, J, Proitsi, P, Lupton, M, Brayne, C, Rubinsztein, D, Gill, M, Lawlor, B, Lynch, A, Brown, K, Passmore, P, Craig, D, Mcguinness, B, Todd, S, Holmes, C, Mann, D, Smith, A, Beaumont, H, Warden, D, Wilcock, G, Love, S, Kehoe, P, Hooper, N, Vardy, E, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Rüther, E, Schürmann, B, Heun, R, Kölsch, H, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Gallacher, J, Hüll, M, Rujescu, D, Giegling, I, Goate, A, Kauwe, J, Cruchaga, C, Nowotny, P, Morris, J, Mayo, K, Sleegers, K, Bettens, K, Engelborghs, S, De Deyn, P, Van Broeckhoven, C, Livingston, G, Bass, N, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Al Chalabi, A, Shaw, C, Tsolaki, M, Singleton, A, Guerreiro, R, Mühleisen, T, Nöthen, M, Moebus, S, Jöckel, K, Klopp, N, Wichmann, H, Pankratz, V, Sando, S, Aasly, J, Barcikowska, M, Wszolek, Z, Dickson, D, Graff Radford, N, Petersen, R, van Duijn, C, Breteler, M, Ikram, M, Destefano, A, Fitzpatrick, A, Lopez, O, Launer, L, Seshadri, S, Berr, C, Campion, D, Epelbaum, J, Dartigues, J, Tzourio, C, Alpérovitch, A, Lathrop, M, Feulner, T, Friedrich, P, Riehle, C, Krawczak, M, Schreiber, S, Mayhaus, M, Nicolhaus, S, Wagenpfeil, S, Steinberg, S, Stefansson, H, Stefansson, K, Snædal, J, Björnsson, S, Jonsson, P, Chouraki, V, Genier Boley, B, Hiltunen, M, Soininen, H, Combarros, O, Zelenika, D, Delepine, M, Bullido, M, Pasquier, F, Mateo, I, Frank Garcia, A, Porcellini, E, Hanon, O, Coto, E, Alvarez, V, Bosco, P, Siciliano, G, Mancuso, M, Panza, F, Solfrizzi, V, Nacmias, B, Sorbi, S, Bossù, P, Piccardi, P, Arosio, B, Annoni, G, Seripa, D, Pilotto, A, Scarpini, E, Galimberti, D, Brice, A, Hannequin, D, Licastro, F, Jones, L, Holmans, P, Jonsson, T, Riemenschneider, M, Morgan, K, Younkin, S, Owen, M, O'Donovan, M, Amouyel, P, Williams, J, Carrasquillo, MM, Hamshere, ML, Pahwa, JS, Lupton, MK, Rubinsztein, DC, Brown, KS, Passmore, PA, McGuinness, B, Smith, AD, Kehoe, PG, Hooper, NM, Vardy, ERLC, Fox, NC, Goate, AM, Kauwe, JSK, Morris, JC, De Deyn, PP, Bass, NJ, McQuillin, A, Shaw, CE, Singleton, AB, Mühleisen, TW, Nöthen, MM, Pankratz, VS, Sando, SB, Aasly, JO, Wszolek, ZK, Dickson, DW, Graff Radford, NR, Petersen, RC, van Duijn, CM, Breteler, MMB, Ikram, MA, DeStefano, AL, Fitzpatrick, AL, Launer, LJ, Feulner, TM, Jonsson, PV, Bullido, MJ, ANNONI, GIORGIO, Holmans, PA, Younkin, SG, Owen, MJ, Williams, J., Hollingworth, P, Harold, D, Sims, R, Gerrish, A, Lambert, J, Carrasquillo, M, Abraham, R, Hamshere, M, Pahwa, J, Moskvina, V, Dowzell, K, Jones, N, Stretton, A, Thomas, C, Richards, A, Ivanov, D, Widdowson, C, Chapman, J, Lovestone, S, Powell, J, Proitsi, P, Lupton, M, Brayne, C, Rubinsztein, D, Gill, M, Lawlor, B, Lynch, A, Brown, K, Passmore, P, Craig, D, Mcguinness, B, Todd, S, Holmes, C, Mann, D, Smith, A, Beaumont, H, Warden, D, Wilcock, G, Love, S, Kehoe, P, Hooper, N, Vardy, E, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Rüther, E, Schürmann, B, Heun, R, Kölsch, H, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Gallacher, J, Hüll, M, Rujescu, D, Giegling, I, Goate, A, Kauwe, J, Cruchaga, C, Nowotny, P, Morris, J, Mayo, K, Sleegers, K, Bettens, K, Engelborghs, S, De Deyn, P, Van Broeckhoven, C, Livingston, G, Bass, N, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Al Chalabi, A, Shaw, C, Tsolaki, M, Singleton, A, Guerreiro, R, Mühleisen, T, Nöthen, M, Moebus, S, Jöckel, K, Klopp, N, Wichmann, H, Pankratz, V, Sando, S, Aasly, J, Barcikowska, M, Wszolek, Z, Dickson, D, Graff Radford, N, Petersen, R, van Duijn, C, Breteler, M, Ikram, M, Destefano, A, Fitzpatrick, A, Lopez, O, Launer, L, Seshadri, S, Berr, C, Campion, D, Epelbaum, J, Dartigues, J, Tzourio, C, Alpérovitch, A, Lathrop, M, Feulner, T, Friedrich, P, Riehle, C, Krawczak, M, Schreiber, S, Mayhaus, M, Nicolhaus, S, Wagenpfeil, S, Steinberg, S, Stefansson, H, Stefansson, K, Snædal, J, Björnsson, S, Jonsson, P, Chouraki, V, Genier Boley, B, Hiltunen, M, Soininen, H, Combarros, O, Zelenika, D, Delepine, M, Bullido, M, Pasquier, F, Mateo, I, Frank Garcia, A, Porcellini, E, Hanon, O, Coto, E, Alvarez, V, Bosco, P, Siciliano, G, Mancuso, M, Panza, F, Solfrizzi, V, Nacmias, B, Sorbi, S, Bossù, P, Piccardi, P, Arosio, B, Annoni, G, Seripa, D, Pilotto, A, Scarpini, E, Galimberti, D, Brice, A, Hannequin, D, Licastro, F, Jones, L, Holmans, P, Jonsson, T, Riemenschneider, M, Morgan, K, Younkin, S, Owen, M, O'Donovan, M, Amouyel, P, Williams, J, Carrasquillo, MM, Hamshere, ML, Pahwa, JS, Lupton, MK, Rubinsztein, DC, Brown, KS, Passmore, PA, McGuinness, B, Smith, AD, Kehoe, PG, Hooper, NM, Vardy, ERLC, Fox, NC, Goate, AM, Kauwe, JSK, Morris, JC, De Deyn, PP, Bass, NJ, McQuillin, A, Shaw, CE, Singleton, AB, Mühleisen, TW, Nöthen, MM, Pankratz, VS, Sando, SB, Aasly, JO, Wszolek, ZK, Dickson, DW, Graff Radford, NR, Petersen, RC, van Duijn, CM, Breteler, MMB, Ikram, MA, DeStefano, AL, Fitzpatrick, AL, Launer, LJ, Feulner, TM, Jonsson, PV, Bullido, MJ, ANNONI, GIORGIO, Holmans, PA, Younkin, SG, Owen, MJ, and Williams, J.

Abstract

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ĝ‰Currency sign 1 × 10 -5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10 -17; including ADGC data, meta P = 5.0 × 10 -21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10 -14; including ADGC data, meta P = 1.2 × 10 -16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10 -4; including ADGC data, meta P = 8.6 × 10 -9), CD33 (GERAD+, P = 2.2 × 10 -4; including ADGC data, meta P = 1.6 × 10 -9) and EPHA1 (GERAD+, P = 3.4 × 10 -4; including ADGC data, meta P = 6.0 × 10 -10). © 2011 Nature America, Inc. All rights reserved.

Published
2011

76. The dopamine beta-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project.

Author

Combarros, O., Warden, D.R., Hammond, N., Cortina-Borja, M., Belbin, O., Lehmann, M.G., Wilcock, G.K., Brown, K., Kehoe, P.G., Barber, R., Coto, E., Alvarez, V., Deloukas, P., Gwilliam, R., Heun, R., Kolsch, H., Mateo, I., Oulhaj, A., Arias Vasquez, A., Schuur, M., Aulchenko, Y.S., Ikram, M.A., Breteler, M.M.B., Duijn, C.M. van, Morgan, K., Smith, A.D., Lehmann, D.J., Combarros, O., Warden, D.R., Hammond, N., Cortina-Borja, M., Belbin, O., Lehmann, M.G., Wilcock, G.K., Brown, K., Kehoe, P.G., Barber, R., Coto, E., Alvarez, V., Deloukas, P., Gwilliam, R., Heun, R., Kolsch, H., Mateo, I., Oulhaj, A., Arias Vasquez, A., Schuur, M., Aulchenko, Y.S., Ikram, M.A., Breteler, M.M.B., Duijn, C.M. van, Morgan, K., Smith, A.D., and Lehmann, D.J.

Abstract

Contains fulltext : 88930.pdf (publisher's version ) (Open Access), BACKGROUND: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine beta-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. METHODS: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. RESULTS: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. CONCLUSIONS: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.

Published
2010

77. The dopamine beta-hydroxylase-1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project

Author

Combarros, O, Warden, DR, Hammond, N, Cortina-Borja, M, Belbin, O, Lehmann, MG, Wilcock, GK, Brown, K, Kehoe, PG, Barber, R, Coto, E, Alvarez, V, Deloukas, P, Gwilliam, R, Heun, R, Kolsch, H, Mateo, I, Oulhaj, A, Arias-Vasquez, A, Schuur, Maaike, Aulchenko, YS, Ikram, Arfan, Breteler, Monique, Duijn, Cornelia, Morgan, K, Smith, AD, Lehmann, DJ, Combarros, O, Warden, DR, Hammond, N, Cortina-Borja, M, Belbin, O, Lehmann, MG, Wilcock, GK, Brown, K, Kehoe, PG, Barber, R, Coto, E, Alvarez, V, Deloukas, P, Gwilliam, R, Heun, R, Kolsch, H, Mateo, I, Oulhaj, A, Arias-Vasquez, A, Schuur, Maaike, Aulchenko, YS, Ikram, Arfan, Breteler, Monique, Duijn, Cornelia, Morgan, K, Smith, AD, and Lehmann, DJ

Abstract

Background: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine beta-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the proinflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. Methods: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. Results: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. Conclusions: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.

Published
2010

78. Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer's disease.

Author

Combarros, O., Duijn, C.M. van, Hammond, N., Belbin, O., Arias Vasquez, A., Cortina-Borja, M., Lehmann, M.G., Aulchenko, Y.S., Schuur, M., Kolsch, H., Heun, R., Wilcock, G.K., Brown, K., Kehoe, P.G., Harrison, R., Coto, E., Alvarez, V., Deloukas, P., Mateo, I., Gwilliam, R., Morgan, K., Warden, D.R., Smith, A.D., Lehmann, D.J., Combarros, O., Duijn, C.M. van, Hammond, N., Belbin, O., Arias Vasquez, A., Cortina-Borja, M., Lehmann, M.G., Aulchenko, Y.S., Schuur, M., Kolsch, H., Heun, R., Wilcock, G.K., Brown, K., Kehoe, P.G., Harrison, R., Coto, E., Alvarez, V., Deloukas, P., Mateo, I., Gwilliam, R., Morgan, K., Warden, D.R., Smith, A.D., and Lehmann, D.J.

Abstract

Contains fulltext : 81701.pdf (publisher's version ) (Open Access), BACKGROUND: Chronic inflammation is a characteristic of Alzheimer's disease (AD). An interaction associated with the risk of AD has been reported between polymorphisms in the regulatory regions of the genes for the pro-inflammatory cytokine, interleukin-6 (IL-6, gene: IL6), and the anti-inflammatory cytokine, interleukin-10 (IL-10, gene: IL10). METHODS: We examined this interaction in the Epistasis Project, a collaboration of 7 AD research groups, contributing DNA samples from 1,757 cases of AD and 6,295 controls. RESULTS: We replicated the interaction. For IL6 rs2069837 AA x IL10 rs1800871 CC, the synergy factor (SF) was 1.63 (95% confidence interval: 1.10-2.41, p = 0.01), controlling for centre, age, gender and apolipoprotein E epsilon4 (APOEepsilon4) genotype. Our results are consistent between North Europe (SF = 1.7, p = 0.03) and North Spain (SF = 2.0, p = 0.09). Further replication may require a meta-analysis. However, association due to linkage disequilibrium with other polymorphisms in the regulatory regions of these genes cannot be excluded. CONCLUSION: We suggest that dysregulation of both IL-6 and IL-10 in some elderly people, due in part to genetic variations in the two genes, contributes to the development of AD. Thus, inflammation facilitates the onset of sporadic AD.

Published
2009

79. Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer's disease

Author

Combarros, O, Duijn, Cornelia, Hammond, N, Belbin, O, Arias-Vasquez, A, Cortina-Borja, M, Lehmann, MG, Aulchenko, YS, Schuur, Maaike, Kolsch, H, Heun, R, Wilcock, GK, Brown, K, Kehoe, PG, Harrison, R, Coto, E, Alvarez, V, Deloukas, P, Mateo, I, Gwilliam, R, Morgan, K, Warden, DR, Smith, AD, Lehmann, DJ, Combarros, O, Duijn, Cornelia, Hammond, N, Belbin, O, Arias-Vasquez, A, Cortina-Borja, M, Lehmann, MG, Aulchenko, YS, Schuur, Maaike, Kolsch, H, Heun, R, Wilcock, GK, Brown, K, Kehoe, PG, Harrison, R, Coto, E, Alvarez, V, Deloukas, P, Mateo, I, Gwilliam, R, Morgan, K, Warden, DR, Smith, AD, and Lehmann, DJ

Abstract

Background: Chronic inflammation is a characteristic of Alzheimer's disease (AD). An interaction associated with the risk of AD has been reported between polymorphisms in the regulatory regions of the genes for the pro-inflammatory cytokine, interleukin-6 (IL-6, gene: IL6), and the anti-inflammatory cytokine, interleukin-10 (IL-10, gene: IL10). Methods: We examined this interaction in the Epistasis Project, a collaboration of 7 AD research groups, contributing DNA samples from 1,757 cases of AD and 6,295 controls. Results: We replicated the interaction. For IL6 rs2069837 AA x IL10 rs1800871 CC, the synergy factor (SF) was 1.63 (95% confidence interval: 1.10-2.41, p = 0.01), controlling for centre, age, gender and apolipoprotein E epsilon 4 (APOE epsilon 4) genotype. Our results are consistent between North Europe (SF = 1.7, p = 0.03) and North Spain (SF = 2.0, p = 0.09). Further replication may require a meta-analysis. However, association due to linkage disequilibrium with other polymorphisms in the regulatory regions of these genes cannot be excluded. Conclusion: We suggest that dysregulation of both IL-6 and IL-10 in some elderly people, due in part to genetic variations in the two genes, contributes to the development of AD. Thus, inflammation facilitates the onset of sporadic AD.

Published
2009

80. Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer’s disease

Author

Rodríguez-Rodríguez, E., primary, Sánchez-Juan, P., additional, Vázquez-Higuera, J. L., additional, Mateo, I., additional, Pozueta, A., additional, Berciano, J., additional, Cervantes, S., additional, Alcolea, D., additional, Martínez-Lage, P., additional, Clarimón, J., additional, Lleó, A., additional, Pastor, P., additional, and Combarros, O., additional

Published
2012
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96. Concordancia electroclínica de la epilepsia con ausencias de la infancia en gemelos monocigóticos

Author

Barrasa J, Trueba Ma, Calleja J, and Combarros O

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Concordance, Spike-and-wave, General Medicine, Audiology, Infantile epilepsy, Electroencephalography, medicine.disease, Molecular analysis, Childhood absence epilepsy, Medicine, Neurology (clinical), business
Abstract

INTRODUCTION AND OBJECTIVE The objective of the study was to analyze the EEG tracings during the seizures of two monozygotic twins, shown on molecular analysis, diagnosed as having infantile epilepsy with absences. The recordings are particularly interesting since the genotypes of the patients are identical. This allowed comparison between the similarities and differences in discharges so that they could be better defined. RESULTS The 3 Hz spike and wave complexes were the same as the classical descriptions in typical absences. No 'W' spike and wave complexes morphology, discharge fragmentation or light induction of the discharges were observed. There was some differences in the duration of absences, which were much shorter in one twin girl. The duration of the seizures was variable, and sometimes similar to that described as characteristic in other types of generalized idiopathic epilepsies with absences. It would seem therefore that the duration of the seizure is not a criterion for differentiation between the different types of generalized idiopathic epilepsies. CONCLUSION Concordance, both clinical and of seizure EEG recordings in our patients confirmed that there is a specific electroclinical phenotype in infantile epilepsy with absences, although individual variations may also occur.

Published
2000

100. Olfaction and imaging biomarkers in premotor LRRK2 G2019S-associated Parkinson disease.

Author

Sierra M, Sánchez-Juan P, Martínez-Rodríguez MI, González-Aramburu I, García-Gorostiaga I, Quirce MR, Palacio E, Carril JM, Berciano J, Combarros O, Infante J, Sierra, Maria, Sánchez-Juan, Pascual, Martínez-Rodríguez, María Isabel, González-Aramburu, Isabel, García-Gorostiaga, Inés, Quirce, María Remedios, Palacio, Enrique, Carril, José Manuel, and Berciano, José

Published
2013
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