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Science. 2019 Nov 29;366(6469):1134-1139. doi: 10.1126/science.aay0793. Epub 2019 Nov 14.

Brain cell type-specific enhancer-promoter interactome maps and disease-risk association.

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Section Molecular Neurobiology, Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands.
3
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
4
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
5
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
6
Flow Cytometry Core Facility, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
7
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
8
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
9
Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, 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.
11
Department of Neurosurgery, University of California, San Diego-Rady Children's Hospital, San Diego, CA 92123, USA.
12
Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
13
The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
14
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA. ckg@ucsd.edu.
15
Department of Cellular and Molecular Medicine, Center for Epigenomics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
#
Contributed equally

Abstract

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. 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. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. 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.

PMID:
31727856
DOI:
10.1126/science.aay0793

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