Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants
Author:
Damotte VincentORCID, van der Lee Sven J, Chouraki Vincent, Grenier-Boley Benjamin, Simino Jeannette, Adams Hieab, Tosto Giuseppe, White Charles, Terzikhan Natalie, Cruchaga Carlos, Knol Maria J., Li Shuo, Schraen Susanna, Grove Megan L., Satizabal ClaudiaORCID, Amin Najaf, Berr Claudine, Younkin Steven, Gottesman Rebecca F., Buée Luc, Beiser Alexa, Knopman David S., Uitterlinden Andre, DeCarli Charles, Bressler Jan, DeStefano Anita, Dartigues Jean-François, Yang Qiong, Boerwinkle Eric, Tzourio Christophe, Fornage Myriam, Ikram M Arfan, Amouyel Philippe, de Jager Phil, Reitz Christiane, Mosley Thomas H, Lambert Jean-Charles, Seshadri Sudha, van Duijn Cornelia,
Abstract
AbstractINTRODUCTIONThere is increasing interest in plasma Aβ as an endophenotype and biomarker of Alzheimer’s disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important processes that determine plasma Aβ measures.METHODSWe included 12,369 non-demented participants derived from eight population-based studies. Imputed genetic data and plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 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 Aβ deposition and AD risk.RESULTSSingle-variant analysis identified associations across APOE for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK and ZNF397. There was suggestive interaction between a BACE1 variant and APOEε4 on brain Aβ deposition.DISCUSSIONIdentification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels both as an endophenotype and a biomarker of AD.
Publisher
Cold Spring Harbor Laboratory
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