期刊
MOLECULAR PSYCHIATRY
卷 19, 期 12, 页码 1326-1335出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2013.185
关键词
A beta; peptides; alzheimer; ctxn3; elderly; gwas; plasma
资金
- National Foundation for Alzheimer's disease and related disorders
- Institut Pasteur de Lille
- Centre National de Genotypage
- Inserm
- FRC (fondation pour la recherche sur le cerveau)
- Rotary
- LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease)
- MEDIALZ Project [11001003]
- ERDF (European Regional Development Fund)
- Conseil Regional Nord Pas de Calais
- Fondation pour la Recherche Medicale
- Caisse Nationale Maladie des Travailleurs Salaries
- Direction Generale de la Sante
- MGEN
- Institut de la Longevite
- Agence Francaise de Securite Sanitaire des Produits de Sante
- Aquitaine Regional Council
- Bourgogne Regional Council
- Fondation de France
- French Ministry of Research/INSERM Cohortes et collections de donnees biologiques programme
- Eisai
- Erasmus Medical Center
- Erasmus University Rotterdam
- Netherlands Organization for Scientific Research (I)
- Netherlands Organization for Health Research and Development (ZonMW)
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Genomics Initiative
- Ministry of Education, Culture and Science
- Ministry of Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Netherlands Consortium for Healthy Ageing
- ZonMW Veni [916.13.054]
- NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756]
- National Institute on Aging (NIA) [AG023629]
- National Center for Advancing Translational Sciences, CTSI [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- Canadian Institutes of Health Research
- NIH [P30 AG010129, K01 AG030514]
Amyloid beta (A beta) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, A beta peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma A beta 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 A beta-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 A beta(1-40) and A beta(1-42) peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P < 1 x 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 A beta(1-42) levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate A beta(1-42) secretion. In conclusion, our study results suggest that plasma A beta peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.
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