Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes

Gloriia Novikova, Manav Kapoor, Julia Tcw, Edsel M. Abud, Anastasia G. Efthymiou, Steven X. Chen, Haoxiang Cheng, John F. Fullard, Jaroslav Bendl, Yiyuan Liu, Panos Roussos, Johan LM Björkegren, Yunlong Liu, Wayne W. Poon, Ke Hao, Edoardo Marcora () and Alison M. Goate ()
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Gloriia Novikova: Icahn School of Medicine at Mount Sinai
Manav Kapoor: Icahn School of Medicine at Mount Sinai
Julia Tcw: Icahn School of Medicine at Mount Sinai
Edsel M. Abud: University of California Irvine
Anastasia G. Efthymiou: Icahn School of Medicine at Mount Sinai
Steven X. Chen: Indiana University School of Medicine
Haoxiang Cheng: Icahn School of Medicine at Mount Sinai
John F. Fullard: Icahn School of Medicine at Mount Sinai
Jaroslav Bendl: Icahn School of Medicine at Mount Sinai
Yiyuan Liu: Icahn School of Medicine at Mount Sinai
Panos Roussos: Icahn School of Medicine at Mount Sinai
Johan LM Björkegren: Icahn School of Medicine at Mount Sinai
Yunlong Liu: Indiana University School of Medicine
Wayne W. Poon: University of California Irvine
Ke Hao: Icahn School of Medicine at Mount Sinai
Edoardo Marcora: Icahn School of Medicine at Mount Sinai
Alison M. Goate: Icahn School of Medicine at Mount Sinai

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.

Date: 2021
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DOI: 10.1038/s41467-021-21823-y

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