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

B K Kunkle; Benjamin Grenier‐Boley; Rebecca Sims; Joshua C. Bis; Adam Christian Naj; Anne Boland; Maria Vronskaya; Sven J. van der Lee; Alexandre Amlie‐Wolf; Céline Bellenguez; Aura Frizzati; Vincent Antoine Chouraki; Eden R. Martin; Kristel Sleegers; Nandini Badarinarayan; Jóhanna Jakobsdóttir; Kara L. Hamilton‐Nelson; R Aloso; Rachel Raybould; Yuning Chen; AB Kuzma; Mikko O. Hiltunen; Taniesha Morgan; Shahzad Ahmad; Badri Narayan Vardarajan; Jacques Epelbaum; Per Hoffmann; Merçé Boada; Gary W. Beecham; J-G Garnier

doi:10.1101/294629

GeneticsbioRxivApr 5, 2018

Preprint

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

B K Kunkle, Benjamin Grenier‐Boley iD, Rebecca Sims iD, Joshua C. Bis iD, Adam Christian Naj iD, Anne Boland iD, Maria Vronskaya, Sven J. van der Lee iD, Alexandre Amlie‐Wolf iD, Céline Bellenguez iD, Aura Frizzati, Vincent Antoine Chouraki iD, Eden R. Martin iD, Kristel Sleegers iD, Nandini Badarinarayan iD, Jóhanna Jakobsdóttir iD, Kara L. Hamilton‐Nelson iD, R Aloso, Rachel Raybould iD, Yuning Chen iD, AB Kuzma, Mikko O. Hiltunen iD, Taniesha Morgan, Shahzad Ahmad iD, Badri Narayan Vardarajan iD, , Clive Holmes iD

Abstract

Late-onset Alzheimers disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3-8. To identify additional LOAD risk loci, the 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 A{beta} 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.

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