A Genome-Wide Association Meta-Analysis Of Plasma A Beta Peptides Concentrations In The Elderly

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.