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  1. Article ; Online: A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly.

    Chouraki, V / De Bruijn, R F A G / Chapuis, J / Bis, J C / Reitz, C / Schraen, S / Ibrahim-Verbaas, C A / Grenier-Boley, B / Delay, C / Rogers, R / Demiautte, F / Mounier, A / Fitzpatrick, A L / Berr, C / Dartigues, J-F / Uitterlinden, A G / Hofman, A / Breteler, M / Becker, J T /
    Lathrop, M / Schupf, N / Alpérovitch, A / Mayeux, R / van Duijn, C M / Buée, L / Amouyel, P / Lopez, O L / Ikram, M A / Tzourio, C / Lambert, J-C

    Molecular psychiatry

    2014  Volume 19, Issue 12, Page(s) 1326–1335

    Abstract: Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that ... ...

    Abstract Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1-40 and Aβ1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.
    MeSH term(s) Aging/blood ; Aging/genetics ; Amyloid beta-Peptides/blood ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Genome-Wide Association Study ; HEK293 Cells ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Peptide Fragments/blood ; Polymorphism, Single Nucleotide ; White People/genetics
    Chemical Substances APP protein, human ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; CTXN3 protein, human ; Membrane Proteins ; Peptide Fragments ; amyloid beta-protein (1-40) ; amyloid beta-protein (1-42)
    Language English
    Publishing date 2014-02-18
    Publishing country England
    Document type Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/mp.2013.185
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A novel Alzheimer disease locus located near the gene encoding tau protein.

    Jun, G / Ibrahim-Verbaas, C A / Vronskaya, M / Lambert, J-C / Chung, J / Naj, A C / Kunkle, B W / Wang, L-S / Bis, J C / Bellenguez, C / Harold, D / Lunetta, K L / Destefano, A L / Grenier-Boley, B / Sims, R / Beecham, G W / Smith, A V / Chouraki, V / Hamilton-Nelson, K L /
    Ikram, M A / Fievet, N / Denning, N / Martin, E R / Schmidt, H / Kamatani, Y / Dunstan, M L / Valladares, O / Laza, A R / Zelenika, D / Ramirez, A / Foroud, T M / Choi, S-H / Boland, A / Becker, T / Kukull, W A / van der Lee, S J / Pasquier, F / Cruchaga, C / Beekly, D / Fitzpatrick, A L / Hanon, O / Gill, M / Barber, R / Gudnason, V / Campion, D / Love, S / Bennett, D A / Amin, N / Berr, C / Tsolaki, Magda / Buxbaum, J D / Lopez, O L / Deramecourt, V / Fox, N C / Cantwell, L B / Tárraga, L / Dufouil, C / Hardy, J / Crane, P K / Eiriksdottir, G / Hannequin, D / Clarke, R / Evans, D / Mosley, T H / Letenneur, L / Brayne, C / Maier, W / De Jager, P / Emilsson, V / Dartigues, J-F / Hampel, H / Kamboh, M I / de Bruijn, R F A G / Tzourio, C / Pastor, P / Larson, E B / Rotter, J I / O'Donovan, M C / Montine, T J / Nalls, M A / Mead, S / Reiman, E M / Jonsson, P V / Holmes, C / St George-Hyslop, P H / Boada, M / Passmore, P / Wendland, J R / Schmidt, R / Morgan, K / Winslow, A R / Powell, J F / Carasquillo, M / Younkin, S G / Jakobsdóttir, J / Kauwe, J S K / Wilhelmsen, K C / Rujescu, D / Nöthen, M M / Hofman, A / Jones, L / Haines, J L / Psaty, B M / Van Broeckhoven, C / Holmans, P / Launer, L J / Mayeux, R / Lathrop, M / Goate, A M / Escott-Price, V / Seshadri, S / Pericak-Vance, M A / Amouyel, P / Williams, J / van Duijn, C M / Schellenberg, G D / Farrer, L A

    Molecular psychiatry

    2015  Volume 21, Issue 1, Page(s) 108–117

    Abstract: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ ( ... ...

    Abstract APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
    MeSH term(s) Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; Chromosomes, Human, Pair 17 ; Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide ; tau Proteins/genetics
    Chemical Substances Apolipoprotein E4 ; MAPT protein, human ; tau Proteins
    Language English
    Publishing date 2015-03-17
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/mp.2015.23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

    Lambert, J C / Ibrahim-Verbaas, C A / Harold, D / Naj, A C / Sims, R / Bellenguez, C / DeStafano, A L / Bis, J C / Beecham, G W / Grenier-Boley, B / Russo, G / Thorton-Wells, T A / Jones, N / Smith, A V / Chouraki, V / Thomas, C / Ikram, M A / Zelenika, D / Vardarajan, B N /
    Kamatani, Y / Lin, C F / Gerrish, A / Schmidt, H / Kunkle, B / Dunstan, M L / Ruiz, A / Bihoreau, M T / Choi, S H / Reitz, C / Pasquier, F / Cruchaga, C / Craig, D / Amin, N / Berr, C / Lopez, O L / De Jager, P L / Deramecourt, V / Johnston, J A / Evans, D / Lovestone, S / Letenneur, L / Morón, F J / Rubinsztein, D C / Eiriksdottir, G / Sleegers, K / Goate, A M / Fiévet, N / Huentelman, M W / Gill, M / Brown, K / Kamboh, M I / Keller, L / Barberger-Gateau, P / McGuiness, B / Larson, E B / Green, R / Myers, A J / Dufouil, C / Todd, S / Wallon, D / Love, S / Rogaeva, E / Gallacher, J / St George-Hyslop, P / Clarimon, J / Lleo, A / Bayer, A / Tsuang, D W / Yu, L / Tsolaki, M / Bossù, P / Spalletta, G / Proitsi, P / Collinge, J / Sorbi, S / Sanchez-Garcia, F / Fox, N C / Hardy, J / Deniz Naranjo, M C / Bosco, P / Clarke, R / Brayne, C / Galimberti, D / Mancuso, M / Matthews, F / Moebus, S / Mecocci, P / Del Zompo, M / Maier, W / Hampel, H / Pilotto, A / Bullido, M / Panza, F / Caffarra, P / Nacmias, B / Gilbert, J R / Mayhaus, M / Lannefelt, L / Hakonarson, H / Pichler, S / Carrasquillo, M M / Ingelsson, M / Beekly, D / Alvarez, V / Zou, F / Valladares, O / Younkin, S G / Coto, E / Hamilton-Nelson, K L / Gu, W / Razquin, C / Pastor, P / Mateo, I / Owen, M J / Faber, K M / Jonsson, P V / Combarros, O / O'Donovan, M C / Cantwell, L B / Soininen, H / Blacker, D / Mead, S / Mosley, T H / Bennett, D A / Harris, T B / Fratiglioni, L / Holmes, C / de Bruijn, R F / Passmore, P / Montine, T J / Bettens, K / Rotter, J I / Brice, A / Morgan, K / Foroud, T M / Kukull, W A / Hannequin, D / Powell, J F / Nalls, M A / Ritchie, K / Lunetta, K L / Kauwe, J S / Boerwinkle, E / Riemenschneider, M / Boada, M / Hiltuenen, M / Martin, E R / Schmidt, R / Rujescu, D / Wang, L S / Dartigues, J F / Mayeux, R / Tzourio, C / Hofman, A / Nöthen, M M / Graff, C / Psaty, B M / Jones, L / Haines, J L / Holmans, P A / Lathrop, M / Pericak-Vance, M A / Launer, L J / Farrer, L A / van Duijn, C M / Van Broeckhoven, C / Moskvina, V / Seshadri, S / Williams, J / Schellenberg, G D / Amouyel, P

    Nature genetics

    2013  Volume 45, Issue 12, Page(s) 1452–1458

    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 ... ...

    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.
    MeSH term(s) Age of Onset ; Aged ; Aged, 80 and over ; Alzheimer Disease/epidemiology ; Alzheimer Disease/genetics ; Case-Control Studies ; Cohort Studies ; Female ; Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study/statistics & numerical data ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide
    Language English
    Publishing date 2013-10-27
    Publishing country United States
    Document type Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.2802
    Database MEDical Literature Analysis and Retrieval System OnLINE

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