Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease

Research output: Contribution to journalArticle

Authors

  • Xianjun Dong
  • Zhixiang Liao
  • David Gritsch
  • Yunfei Bai
  • Joseph J Locascio
  • Boris Guennewig
  • Ganqiang Liu
  • Cornelis Blauwendraat
  • Tao Wang
  • Charles H Adler
  • John C Hedreen
  • Richard L M Faull
  • Matthew P Frosch
  • Peter T Nelson
  • Patrizia Rizzu
  • Antony A Cooper
  • Peter Heutink
  • Thomas G Beach
  • John S Mattick
  • Clemens R Scherzer

External organisations

  • Center for Advanced Parkinson's Disease Research of Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA.
  • Cancer Bioinfomatics Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
  • Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00014, Finland; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • St Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia.
  • German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
  • Harvard Brain Tissue Resource Center, McLean Hospital, Harvard Medical School, Boston, MA, USA.
  • Department of Medicine, University of Auckland, Auckland, New Zealand; and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
  • C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA, USA.
  • Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
  • Banner Sun Health Research Institute, Sun City, AZ, USA.
  • Program in Neuroscience, Harvard Medical School, Boston, MA, USA. cscherzer@rics.bwh.harvard.edu.

Abstract

Enhancers function as DNA logic gates and may control specialized functions of billions of neurons. Here we show a tailored program of noncoding genome elements active in situ in physiologically distinct dopamine neurons of the human brain. We found 71,022 transcribed noncoding elements, many of which were consistent with active enhancers and with regulatory mechanisms in zebrafish and mouse brains. Genetic variants associated with schizophrenia, addiction, and Parkinson's disease were enriched in these elements. Expression quantitative trait locus analysis revealed that Parkinson's disease-associated variants on chromosome 17q21 cis-regulate the expression of an enhancer RNA in dopamine neurons. This study shows that enhancers in dopamine neurons link genetic variation to neuropsychiatric traits.

Details

Original languageEnglish
Pages (from-to)1482-1492
Number of pages11
JournalNature Neuroscience
Volume21
Issue number10
Publication statusPublished - Oct 2018