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Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates AB, tau, immunity and lipid processing

Abstract: Risk for late-onset Alzheimer?s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer?s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A? processing are associated not only with early-onset autosomal dominant Alzheimer?s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10?7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

 Fuente: Nat Genet 2019 Mar;51(3):414-430

 Editorial: Nature Publishing Group

 Año de publicación: 2019

 Nº de páginas: 22

 Tipo de publicación: Artículo de Revista

 DOI: 10.1038/s41588-019-0358-2

 ISSN: 1061-4036,1546-1718

 Url de la publicación: https://doi.org/10.1038/s41588-019-0358-2

Autoría

KUNKLE, BRIAN W.

GRENIER-BOLEY, BENJAMIN

SIMS, REBECCA

BIS, JOSHUA C.

DAMOTTE, VINCENT

NAJ, ADAM C.

BOLAND, ANNE

VRONSKAYA, MARIA

LEE, SVEN J. VAN DER

AMLIE-WOLF, ALEXANDRE

BELLENGUEZ, CÉLINE

FRIZATTI, AURA

CHOURAKI, VINCENT

MARTIN, EDEN R.

SLEEGERS, KRISTEL

BADARINARAYAN, NANDINI

JAKOBSDOTTIR, JOHANNA

JOSE IGNACIO MATEO FERNANDEZ

RODRÍGUEZ RODRÍGUEZ, ELOY

PASCUAL SANCHEZ JUAN