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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 Aβ1-40 and Aβ1-42 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 Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 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.

Original publication

DOI

10.1038/mp.2013.185

Type

Journal article

Journal

Molecular psychiatry

Publication Date

12/2014

Volume

19

Pages

1326 - 1335

Addresses

1] INSERM U744, Lille, France [2] Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Lille, France.

Keywords

Alzheimer's Disease Neuroimaging Initiative, Humans, Peptide Fragments, Amyloid beta-Protein Precursor, Membrane Proteins, Aging, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Genome-Wide Association Study, Amyloid beta-Peptides, HEK293 Cells