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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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