| Literature DB >> 31727856 |
Alexi Nott1, Inge R Holtman1,2, Nicole G Coufal3,4, Johannes C M Schlachetzki1, Miao Yu5, Rong Hu5, Claudia Z Han1, Monique Pena3, Jiayang Xiao3, Yin Wu3, Zahara Keulen3, Martina P Pasillas1, Carolyn O'Connor6, Christian K Nickl1, Simon T Schafer3, Zeyang Shen1,7, Robert A Rissman8,9, James B Brewer8, David Gosselin1,10, David D Gonda11, Michael L Levy11, Michael G Rosenfeld12, Graham McVicker13, Fred H Gage2, Bing Ren4,13, Christopher K Glass14,15.
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.Entities:
Mesh：
Substances：
Year: 2019 PMID： 31727856 PMCID： PMC7028213 DOI： 10.1126/science.aay0793
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728