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Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Sims, R, Vronskaya, M, Frizatti, A, Badarinarayan, N, Raybould, R, Morgan, T, Gerrish, A, Denning, N, Hollingworth, P, Marshall, Rachel, Meggy, A, Menzies, G, Leonenko, G, Grozeva, D, O'Donovan, M C, Jones, L, Owen, M J, Price, Vaughn, Williams, J, Cushion, T D, Bayer, A and Gallacher, J 2018. Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing. bioRxiv 10.1101/294629

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Abstract

Late-onset Alzheimers disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly, and risk is partially driven by genetics. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS). To identify additional LOAD risk loci, we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Abeta processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 x 10-7) indicating that additional rare variants remain to be identified.

Item Type: Article
Date Type: Published Online
Status: Unpublished
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Full list of authors will show on the DOI Link.
Publisher: Cornell University
Date of First Compliant Deposit: 14 November 2018
Date of Acceptance: 31 October 2018
Last Modified: 19 Jul 2019 14:42
URI: http://orca.cf.ac.uk/id/eprint/116728

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