Genome-wide Association Study Links APOEϵ4 and BACE1 Variants with Plasma Amyloid β Levels

Chouraki, V.; van der Lee, S. J.; Grenier-Boley, B.; Simino, J.; Adams, H.; Tosto, G.; White, C.; Terzikhan, N.; Cruchaga, C.; Knol, M. J.; Li, S.; Schraen, S.; Grove, M. L.; Satizabal, C. L.; Amin, N.; Berr, C.; Younkin, S.; Alzheimer's Disease Neuroimaging Initiative,; Gottesman, R. F.; Buee, L.; Beiser, A.; Knopman, D. S.; Uitterlinden, A.; DeCarli, C.; Bressler, J.; DeStefano, A.; Dartigues, J.-F.; Yang, Q.; Boerwinkle, E.; Tzourio, C.; Fornage, M.; Ikram, M. A.; Amouyel, P.; de Jager, P.; Reitz, C.; Mosley, T. H.; Lambert, J.-C.; Seshadri, S.; van Duijn, C.

doi:10.1101/194266

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bioRxiv · 10.1101/194266

Genome-wide Association Study Links APOEϵ4 and BACE1 Variants with Plasma Amyloid β Levels

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Abstract

INTRODUCTIONThere is increasing interest in plasma A{beta} as an endophenotype and biomarker of Alzheimers disease (AD). Identifying the genetic determinants of plasma A{beta} levels may elucidate important processes that determine plasma A{beta} measures. METHODSWe included 12,369 non-demented participants derived from eight population-based studies. Imputed genetic data and plasma A{beta}1-40, A{beta}1-42 levels and A{beta}1-42/A{beta}1-40 ratio were used to perform genome-wide association studies, gene-based and pathway analyses. Significant variants and genes were followed-up for the association with PET A{beta} deposition and AD risk. RESULTSSingle-variant analysis identified associations across APOE for A{beta}1-42 and A{beta}1-42/A{beta}1-40 ratio, and BACE1 for A{beta}1-40. Gene-based analysis of A{beta}1-40 additionally identified associations for APP, PSEN2, CCK and ZNF397. There was suggestive interaction between a BACE1 variant and APOE{varepsilon}4 on brain A{beta} deposition. DISCUSSIONIdentification of variants near/in known major A{beta}-processing genes strengthens the relevance of plasma-A{beta} levels both as an endophenotype and a biomarker of AD.

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Chouraki, V., van der Lee, S. J., Grenier-Boley, B., Simino, J., Adams, H., Tosto, G., White, C., Terzikhan, N., Cruchaga, C., Knol, M. J., Li, S., Schraen, S., Grove, M. L., Satizabal, C. L., Amin, N., Berr, C., Younkin, S., Alzheimer's Disease Neuroimaging Initiative,, Gottesman, R. F., Buee, L., Beiser, A., Knopman, D. S., Uitterlinden, A., DeCarli, C., Bressler, J., DeStefano, A., Dartigues, J.-F., Yang, Q., Boerwinkle, E., Tzourio, C., Fornage, M., Ikram, M. A., Amouyel, P., de Jager, P., Reitz, C., Mosley, T. H., Lambert, J.-C., Seshadri, S., van Duijn, C.. 2017-09-27. Genome-wide Association Study Links APOEϵ4 and BACE1 Variants with Plasma Amyloid β Levels. https://doi.org/10.1101/194266

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