A genome-wide association meta-analysis of plasma Aβ 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.