Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes
| Autor: | Manav Kapoor, Wayne W. Poon, Edsel M. Abud, John F. Fullard, Jaroslav Bendl, Yunlong Liu, Alison Goate, Edoardo Marcora, Julia Tcw, Panos Roussos, Anastasia G. Efthymiou, Johan L.M. Björkegren, Ke Hao, Yiyuan Liu, Steven X. Chen, Gloriia Novikova, Haoxiang Cheng |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Aging Myeloid Neuroimmunology General Physics and Astronomy Genome-wide association study Neurodegenerative Regulatory Sequences Nucleic Acid Alzheimer's Disease Genome informatics 0302 clinical medicine 2.1 Biological and endogenous factors Myeloid Cells Aetiology Epigenomics Genetics Regulation of gene expression Multidisciplinary Functional genomics Genomics Alzheimer's disease medicine.anatomical_structure Regulatory sequence Neurological Microglia Biotechnology Science Induced Pluripotent Stem Cells Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Alzheimer Disease Acquired Cognitive Impairment medicine Humans Genetic Predisposition to Disease Gene Alleles Nucleic Acid Prevention Macrophages Human Genome Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) General Chemistry Stem Cell Research Brain Disorders 030104 developmental biology Gene Expression Regulation Dementia Transcriptome Regulatory Sequences 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Nature Communications Nature communications, vol 12, iss 1 Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-21823-y |
| Popis: | 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. This study integrates Alzheimer’s disease (AD) GWAS data with myeloid cell genomics, and reports that myeloid active enhancers are most burdened by AD risk alleles. The authors also nominate candidate causal regulatory elements, variants and genes that likely modulate the risk for AD. |
| Databáze: | OpenAIRE |
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