A genome-wide association meta-analysis of plasma A[beta] peptides concentrations in the elderly.
Chouraki, V 1,2,3; De Bruijn, R FAG 4,5,6; Chapuis, J 1,2,3; Bis, J C 7; Reitz, C 8,9,10; Schraen, S 3,11,12; Ibrahim-Verbaas, C A 4,5; Grenier-Boley, B 1,2,3; Delay, C 1,2,3; Rogers, R 8; Demiautte, F 1,2,3; Mounier, A 1,2,3; Fitzpatrick, A L 7; The Alzheimer's Disease Neuroimaging Initiative 23; Berr, C 13; Dartigues, J-F 14; Uitterlinden, A G 6,15; Hofman, A 4,6; Breteler, M 4,16; Becker, J T 17; Lathrop, M 18,19; Schupf, N 9; Alperovitch, A 20; Mayeux, R 8,21; van Duijn, C M 4,6; Buee, L 3,11,12; Amouyel, P 1,2,3,12; Lopez, O L 17; Ikram, M A 4,5,6,22; Tzourio1, C 4,20; Lambert, J-C 1,2,3
[Article]
Molecular Psychiatry.
19(12):1326-1335, December 2014.
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: 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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