Genetic risk for Alzheimer's disease is concentrated in specific macrophage and microglial transcriptional networks

Genome Medicine
Katherine E TanseyMatthew J Hill

Abstract

Genome-wide association studies of Alzheimer's disease (AD) have identified a number of significant risk loci, the majority of which lie in non-coding regions of the genome. The lack of causal alleles and considerable polygenicity remains a significant barrier to translation into mechanistic understanding. This includes identifying causal variants and the cell/tissue types in which they operate. A fuller understanding of the cell types and transcriptional networks involved in AD genetic risk mechanisms will provide important insights into pathogenesis. We assessed the significance of the overlap between genome-wide significant AD risk variants and sites of open chromatin from data sets representing diverse tissue types. We then focussed on macrophages and microglia to investigate the role of open chromatin sites containing motifs for specific transcription factors. Partitioned heritability using LDscore regression was used to investigate the contribution of specific macrophage and microglia transcription factor motif-containing open chromatin sites to the heritability of AD. AD risk single nucleotide polymorphisms (SNPs) are preferentially located at sites of open chromatin in immune cells, particularly monocytes (z score = 4.4...Continue Reading

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Citations

Nov 18, 2018·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Sarah R Anderson, Monica L Vetter
Sep 29, 2019·Journal of Alzheimer's Disease : JAD·Alexandre Amlie-WolfGerard D Schellenberg
May 14, 2019·Alzheimer's & Dementia : Diagnosis, Assessment & Disease Monitoring·Thomas M Lancaster
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Jun 5, 2021·Nature Genetics·Adam M H YoungDaniel J Gaffney
Jun 3, 2021·International Journal of Molecular Sciences·Gaylia Jean Harry
Jul 6, 2021·Frontiers in Neuroscience·Ann M SaundersWilliam Kirby Gottschalk

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Methods Mentioned

BETA
immunoprecipitation
ChIP-seq

Software Mentioned

chromHMM
HOMER
SNPsnap
ENCODE
bwa
BEDTools
Roadmap Epigenomics
Segway
Epigenomics

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