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

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Abstract

Non-coding 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 non-coding 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 genes likely to be influenced by non-coding variants in AD and suggest the probable cell types in which they function.

One Sentence Summary:

Identification of cell type-specific regulatory elements in the human brain enables interpretation of non-coding GWAS risk variants.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0404511

Journal ID (pubmed-jr-id): 7473

Journal ID (nlm-ta): Science

Journal ID (iso-abbrev): Science

Title: Science (New York, N.Y.)

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date Nihms-submitted: 1 February 2020

Publication date (Electronic): 14 November 2019

Publication date (Print): 29 November 2019

Publication date PMC-release: 18 February 2020

Volume: 366

Issue: 6469

Pages: 1134-1139

Affiliations

[1 ]Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

[2 ]Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

[3 ]Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.

[4 ]Ludwig Institute for Cancer Research, La Jolla, CA, USA.

[5 ]Flow Cytometry Core Facility, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA

[6 ]Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

[7 ]Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.

[8 ]Veterans Affairs San Diego Healthcare System San Diego, CA, USA.

[9 ]Centre de Recherche du Centre Hospitalier Universitaire de Québec–Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, Canada.

[10 ]Department of Neurosurgery, University of California, San Diego–Rady Children’s Hospital, San Diego, CA 92123, USA.

[11 ]Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA, USA.

[12 ]The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

[13 ]Department of Cellular and Molecular Medicine, Center for Epigenomics, University of California, San Diego School of Medicine, La Jolla, CA, USA.

[14 ]Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Author notes

[† ]Correspondence to: ckg@ 123456ucsd.edu

[*]

These authors contributed equally to this work.

Author contributions: A.N., N.G.C., J.C.M.S., and C.K.G. conceived the study. N.G.C. coordinated tissue acquisition. D.D.G., and M.L.L. resected brain tissue. A.N., C.K.N., M.P.P. and D.G. isolated nuclei and cells. N.G.C., M.P., J.X., Y.W., Z.K. and C.O performed PSC experiments. A.N., M.Y. and R.H prepared sequencing libraries. I.R.H., A.N., and Z.S analyzed datasets. A.N., I.R.H., C.K.G. wrote the manuscript, with contributions from N.G.C., C.Z.H., J.C.M.S., M.G.R., F.H.G. and B.R.

Article

Accession ID: PMC7028213 Pmcid ID: PMC7028213 Pmc-uid ID: 7028213 Manuscript ID: nihpa1066836

DOI: 10.1126/science.aay0793

PMC ID: 7028213

PubMed ID: 31727856

SO-VID: 9704324a-a9ed-4c3e-a5be-d234404aa8a5

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

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