Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes.
Gloriia NovikovaManav KapoorJulia TcwEdsel M AbudAnastasia G EfthymiouSteven X ChenHaoxiang ChengJohn F FullardJaroslav BendlYiyuan LiuPanagiotis RoussosJohan L M BjorkegrenYunlong LiuWayne W PoonKe HaoEdoardo MarcoraAlison Mary GoatePublished in: Nature communications (2021)
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.
Keyphrases
- gene expression
- genome wide
- dendritic cells
- bone marrow
- transcription factor
- acute myeloid leukemia
- stem cells
- mass spectrometry
- genome wide association
- multiple sclerosis
- ms ms
- endothelial cells
- rna seq
- induced apoptosis
- genome wide association study
- spinal cord injury
- single cell
- signaling pathway
- genome wide identification
- high resolution
- bioinformatics analysis
- neuropathic pain
- cell proliferation
- drug induced
- brain injury
- resting state
- blood brain barrier
- pi k akt
- functional connectivity
- cerebral ischemia
- liquid chromatography