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
By
Vincent Damotte,
Sven J. van der Lee,
Vincent Chouraki,
Benjamin Grenier-Boley,
Jeannette Simino,
Hieab Adams,
Giuseppe Tosto,
Charles White,
Natalie Terzikhan,
Carlos Cruchaga,
Maria J. Knol,
Shuo Li,
Susanna Schraen,
Megan L Grove,
Claudia L. Satizabal,
Najaf Amin,
Claudine Berr,
Steven Younkin,
Alzheimer's Disease Neuroimaging Initiative,
Rebecca F. Gottesman,
Luc Buee,
Alexa Beiser,
David S. Knopman,
Andre Uitterlinden,
Charles DeCarli,
Jan Bressler,
Anita DeStefano,
Jean-François Dartigues,
Qiong Yang,
Eric Boerwinkle,
Christophe Tzourio,
Myriam Fornage,
Mohammad Arfan Ikram,
Philippe Amouyel,
Phil de Jager,
Christiane Reitz,
Thomas H Mosley,
Jean-Charles Lambert,
Sudha Seshadri,
Cornelia van Duijn
Posted 27 Sep 2017
bioRxiv DOI: 10.1101/194266
INTRODUCTION: There is increasing interest in plasma A{beta} as an endophenotype and biomarker of Alzheimer's disease (AD). Identifying the genetic determinants of plasma A{beta} levels may elucidate important processes that determine plasma A{beta} measures. METHODS: We 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. RESULTS: Single-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. DISCUSSION: Identification 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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