A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

• Published in: Molecular psychiatry Vol. 19; no. 12; pp. 1326 - 1335
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2014; Nature Publishing Group
• Subjects: 631/1647/2217/2138; 692/420; 692/699/375/365/1283; 692/700/1518; Adult and adolescent clinical studies; Aged; Aging - blood; Aging - genetics; Alzheimer's disease; Amyloid beta-Peptides - blood; Amyloid beta-protein; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Analysis; Axon guidance; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Genetic aspects; Genetic factors; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; HEK293 Cells; Humans; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Meta-analysis; Metabolism; Metabolites; Neurodegenerative diseases; Neurology; Neurosciences; Older people; Organic mental disorders. Neuropsychology; original-article; Peptide Fragments - blood; Peptides; Pharmacotherapy; Plasma; Polymorphism, Single Nucleotide; Protein turnover; Psychiatry; Psychological aspects; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Risk factors; Senile plaques; White People - genetics; Netherlands; alzheimer; Aβ; gwas; ctxn3; elderly; peptides; plasma; Human; Nervous system diseases; Alzheimer disease; Review; Cerebral disorder; Metaanalysis; Central nervous system disease; Degenerative disease; Elderly
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2013.185

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 Aβ 1–40 and Aβ 1 –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 Aβ 1 –42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ 1 –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.