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

By B. Kunkle, B. Grenier‐Boley, R. Sims, J. Bis, V. Damotte, A. Naj, A. Boland, M. Vronskaya, S. J. van der Lee, A. Amlie-Wolf and 457 more. Nature Genetics, 2019

2,422 citations recorded by the source corpus.

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 Aβ 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. Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Subfields: Genetics, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/14432239a5ce62e6668d87082679da34186f7499

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In Genetics

1. J. Long
2. D. Holtzman

In Molecular Biology

1. J. Long
2. Lon S. Schneider
3. Marie Odile Habert
4. Jeffrey L. Cummings
5. Kaj Blennow
6. Gil D. Rabinovici
7. D. Holtzman

In Physiology

1. J. Long
2. D. Holtzman
3. Kaj Blennow
4. Yaakov Stern
5. Marie Odile Habert
6. Bruno Dubois
7. Jeffrey L. Cummings
8. Gil D. Rabinovici

Citations in the corpus

• Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group (2021, background): “…pathways (genetic protection and risk factors regarding tau binding proteins and amyloid precursor protein metabolism; protection and risk factors related to immunity, endocytosis, and lipid metabolism 26–30 ; newly described brain cellular senescence mechanisms 31 ), and co-pathology.”
• Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “The strength of this association has been confirmed in numerous clinical, pathological, epidemiological, genome-wide association (GWAS) and whole genome sequencing studies over the years (Kunkle et al., 2019).”