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

Xianjun Dong, Zhixiang Liao, David Gritsch, Yavor Hadzhiev, 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. MattickFerenc Müller, Clemens R. Scherzer

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1482-1492
Number of pages11
JournalNature Neuroscience
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2018

ASJC Scopus subject areas

  • Neuroscience(all)

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    Dong, X., Liao, Z., Gritsch, D., Hadzhiev, Y., Bai, Y., Locascio, J. J., Guennewig, B., Liu, G., Blauwendraat, C., Wang, T., Adler, C. H., Hedreen, J. C., Faull, R. L. M., Frosch, M. P., Nelson, P. T., Rizzu, P., Cooper, A. A., Heutink, P., Beach, T. G., ... Scherzer, C. R. (2018). Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease. Nature Neuroscience, 21(10), 1482-1492. https://doi.org/10.1038/s41593-018-0223-0