Title | Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Novikova G, Kapoor M, Tcw J, Abud EM, Efthymiou AG, Chen SX, Cheng H, Fullard JF, Bendl J, Liu Y, Roussos P, Björkegren JLm, Liu Y, Poon WW, Hao K, Marcora E, Goate AM |
Journal | Nat Commun |
Volume | 12 |
Issue | 1 |
Pagination | 1610 |
Date Published | 2021 03 12 |
ISSN | 2041-1723 |
Keywords | Alleles, Alzheimer Disease, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Induced Pluripotent Stem Cells, Macrophages, Microglia, Myeloid Cells, Regulatory Sequences, Nucleic Acid, Transcriptome |
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. |
DOI | 10.1038/s41467-021-21823-y |
Pubmed Link | https://www.ncbi.nlm.nih.gov/pubmed/33712570?dopt=Abstract |
page_expo | Internal |
Alternate Journal | Nat Commun |
PubMed ID | 33712570 |
PubMed Central ID | PMC7955030 |
Grant List | R01 AG050986 / AG / NIA NIH HHS / United States U01 AG052411 / AG / NIA NIH HHS / United States R01 ES029212 / ES / NIEHS NIH HHS / United States K01 AG062683 / AG / NIA NIH HHS / United States U01 AG058635 / AG / NIA NIH HHS / United States RF1 AG054011 / AG / NIA NIH HHS / United States F31 AG059337 / AG / NIA NIH HHS / United States R01 HL125863 / HL / NHLBI NIH HHS / United States |
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