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

Alexi Nott, Inge R. Holtman, Nicole G. Coufal, Johannes C. M. Schlachetzki, Miao Yu, Rong Hu, Claudia Z. Han, Monique Pena, Jiayang Xiao, Yin Wu, Zahara Keulen, Martina P. Pasillas, Carolyn O'Connor, Christian K. Nickl, Simon T. Schafer, Zeyang Shen, Robert A. Rissman, James B. Brewer, David Gosselin, David D. GondaMichael L. Levy, Michael G. Rosenfeld, Graham McVicker, Fred H. Gage, Bing Ren, Christopher K. Glass*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

79 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1134-1139
Number of pages50
JournalScience
Volume366
Issue number6469
DOIs
Publication statusPublished - 29-Nov-2019

Keywords

  • GENOME
  • ASTROCYTES
  • GENERATION
  • VARIANTS
  • REVEALS
  • LOCI

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