A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly.
A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly.
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DOI：
10.1038/mp.2013.185
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发表时间：
2014-12
影响因子：
11
通讯作者：
Lambert, J-C
中科院分区：
文献类型：
--
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
老年斑是阿尔茨海默病（Alzheimer disease，AD）的主要病理标志之一，其主要成分是β淀粉样蛋白（Amyloid beta，Aβ）。然而，Aβ肽的功能尚未完全了解，并且似乎是高度多效性的。我们假设血浆Aβ肽浓度可能是全基因组关联研究（GWAS）的合适内表型，该研究旨在（i）确定参与淀粉样前体蛋白代谢的新遗传因子，（ii）突出相关Aβ相关生理和病理生理过程。因此，我们对4项研究进行了全基因组关联荟萃分析，共计3528名欧洲血统的健康个体，并对他们的血浆Aβ1-40和Aβ1-42肽水平进行了定量。虽然我们没有观察到任何全基因组显著性位点，但我们确定了18个提示性位点（P<1 × 10−5）。富集途径分析揭示了主要参与神经元功能的典型途径，例如，轴突引导信号。我们还评估了与血浆Aβ1-42水平最密切相关的基因（皮质素3，CTXN 3）对体外APP代谢的生物学影响，发现该基因蛋白能够调节Aβ1-42分泌。总之，我们的研究结果表明，血浆Aβ肽水平是GWAS的有效内表型，可用于表征APP及其代谢产物的代谢和功能。
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.
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影响因子：
11
作者：
通讯作者：
--
DOI：
10.1016/j.jalz.2012.01.001
发表时间：
2012-07
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Figurski MJ;Waligórska T;Toledo J;Vanderstichele H;Korecka M;Lee VM;Trojanowski JQ;Shaw LM;Alzheimer’s Disease Neuroimaging Initiative
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
影响因子：
3.9
作者：
Ertekin-Taner, N;Allen, M;Younkin, SG
通讯作者：
Younkin, SG
影响因子：
3.5
作者：
Ertekin-Taner, N;Ronald, J;Younkin, S
通讯作者：
Younkin, S
影响因子：
2.5
作者：
Giedraitis, Vilmantas;Sundelof, Johan;Lannfelt, Lars
通讯作者：
Lannfelt, Lars