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Abstract: Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
Fuente: Alzheimers Dement . 2019, 15(10), 1333-1347
Editorial: John Wiley & Sons
Año de publicación: 2019
Nº de páginas: 15
Tipo de publicación: Artículo de Revista
DOI: 10.1016/j.jalz.2019.06.4950
ISSN: 1552-5260,1552-5279
Url de la publicación: https://doi.org/10.1016/j.jalz.2019.06.4950
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MORENO-GRAU, SONIA
ROJAS, ITZIAR DE
HERNÁNDEZ, ISABEL
QUINTELA, INÉS
MONTRREAL, LAURA
ALEGRET, MONTSERRAT
HERNÁNDEZ-OLASAGARRE, BEGOÑA
MADRID, LAURA
GONZÁLEZ-PEREZ, ANTONIO
MAROÑAS, OLALLA
ROSENDE-ROCA, MAITÉE
MAULEÓN, ANA
VARGAS, LILIANA
LAFUENTE, ASUNCIÓN
ABDELNOUR, CARLA
RODRÍGUEZ-GÓMEZ, OCTAVIO
GIL, SILVIA
SANTOS SANTOS, MIGUEL ÁNGEL
ESPINOSA, ANA
PASCUAL SANCHEZ JUAN
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