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Largest GWAS (N=1,126,563) of Alzheimer’s Disease Implicates Microglia and Immune Cells

Authors :
Tore Wergeland Meisingset
Kari Stefansson
Shahram Bahrami
Sigurdur H. Magnusson
Tormod Fladby
Ingunn Bosnes
Lavinia Athanasiu
Danielle Posthuma
Sigrid Botne Sando
Stephan Ripke
Linda M. Pedersen
Amy E Martinsen
Dag Aarsland
Ole Kristian Drange
Henrik Zetterberg
Alexey A. Shadrin
Margda Waern
Steinunn Thordardottir
Sigrid Børte
Wei Zhou
Kristian Hveem
Marianne Bakke Johnsen
Julia M. Sealock
Eystein Stordal
Geir Selbæk
Silke Kern
John-Anker Zwart
Iris E. Jansen
Palmi V. Jonsson
Ole A. Andreassen
Ingvild Saltvedt
Ingmar Skoog
Maiken Elvestad Gabrielsen
Cristen J. Willer
Chandra A. Reynolds
Ingun Ulstein
Arvid Rongve
Anne Heidi Skogholt
Douglas P Wightman
Richard Dobson
Anna Zettergren
Lea K. Davis
Nancy L. Pedersen
Ida K. Karlsson
Srdjan Djurovic
Kaj Blennow
Laurent F. Thomas
Latha Velayudhan
Angela Hodges
Bendik S. Winsvold
Jon Snaedal
Lars G. Fritsche
Hreinn Stefansson
Petra Proitsi
Jeanne E. Savage
Jonas B. Nielsen
Geir Bråthen
Publication Year :
2020
Publisher :
Cold Spring Harbor Laboratory, 2020.

Abstract

SummaryLate-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases1. Late-onset Alzheimer’s disease is caused by a combination of many genetic variants with small effect sizes and environmental influences. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified2,3. Here we show that increased sample sizes allowed for identification of seven novel genetic loci contributing to Alzheimer’s disease. We highlighted eight potentially causal genes where gene expression changes are likely to explain the association. Human microglia were found as the only cell type where the gene expression pattern was significantly associated with the Alzheimer’s disease association signal. Gene set analysis identified four independent pathways for associated variants to influence disease pathology. Our results support the importance of microglia, amyloid and tau aggregation, and immune response in Alzheimer’s disease. We anticipate that through collaboration the results from this study can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants which contribute to Alzheimer’s pathology. Furthermore, the increased understanding of the mechanisms that mediate the effect of genetic variants on disease progression will help identify potential pathways and gene-sets as targets for drug development.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........19ccd596040591a0324fb155accdfb4c
Full Text :
https://doi.org/10.1101/2020.11.20.20235275