A genome-wide association meta-analysis of plasma A beta peptides concentrations in the elderly

作者：Chouraki V; De Bruijn R F A G; Chapuis J; Bis J C; Reitz C; Schraen S; Ibrahim Verbaas C A; Grenier Boley B; Delay C; Rogers R; Demiautte F; Mounier A; Fitzpatrick A L; Berr C; Dartigues J F; Uitterlinden A G; Hofman A; Breteler M; Becker J T; Lathrop M; Schupf N; Alperovitch A; Mayeux R; van Duijn C M; Buee L; Amouyel P; Lopez O L; Ikram M A; Tzourio C; Lambert J C^*

来源：Molecular Psychiatry, 2014, 19(12): 1326-1335.

DOI：10.1038/mp.2013.185

• A beta
• peptides
• alzheimer
• ctxn3
• elderly
• gwas
• plasma

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.

• 出版日期2014-12
• 单位中国地震局