(E) Protein expression of BIN1 in control andīIN1 enh_del PSCs, microglia, neurons andĪstrocytes determined as Western blot BIN1/GAPDH mean gray intensity. (D) Western blot of BIN1 and GAPDH inĬontrol and BIN1 enh_del PSC-derived microglia (top)Īnd neurons (bottom). Neurons (N = 6,5) and astrocytes (N = 4,5) as RNA-seq TPM. (C) BIN1 gene expression in control andīIN1 enh_del PSCs (N = 8,7), microglia (N = 6,5), PSCs, microglia, neurons and astrocytes in control andīIN1 enh_del lines stained for the indicated cell The AD GWAS track shows meta-analysis p-values of stage 2 variantsīlue dots are fine mapped 95% credible set variants. Region, highlighted pink microglia-specific enhancer region, highlighted in H3K4me3 ChIP-seq and PLAC-seq in brain cell types. (A) UCSC browser of theīIN1 locus showing AD-risk variants, ATAC-seq, H3K27ac, Variant affects microglia BIN1 expression. GWAS track shows meta-analysis p-values of stage 2 variants (18) line indicates p-value = 5e-8 blue dots areĭeletion of a microglia-specific enhancer harboring a lead AD-risk GWAS-assigned genes and (E) cell type-specific gene regulatory regions. (C)-(E) UCSC browser of interactions at AD-risk lociĭemonstrating (C) reassignment of GWAS-assigned genes, (D) extension of (B) Chow-Ruskey plot of genes that are GWAS-assignedĪnd PLAC-seq linked to AD-risk credible set variants in microglia, neurons and Values of high-confidence AD variants identified by fine mapping (Kunkle, stageġ) with log10 p-value 0.2. Regions (black bars) and PLAC-seq interactions (black loops). Showing microglia enhancers (gold bars), promoters (turquoise), open chromatin Government Works.Įxpanded gene network of AD-risk loci. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.Ĭopyright © 2019 The Authors, some rights reserved exclusive licensee American Association for the Advancement of Science. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain.
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Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. 15 Department of Cellular and Molecular Medicine, Center for Epigenomics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA. 14 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.13 The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.12 Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.11 Department of Neurosurgery, University of California, San Diego-Rady Children's Hospital, San Diego, CA 92123, USA.10 Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada.9 Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.8 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.7 Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.6 Flow Cytometry Core Facility, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.5 Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.4 Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.3 Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.2 Section Molecular Neurobiology, Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands.1 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.