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 Mattick; Ferenc Müller; Clemens R Scherzer

doi:10.1038/s41593-018-0223-0

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

Nat Neurosci. 2018 Oct;21(10):1482-1492. doi: 10.1038/s41593-018-0223-0. Epub 2018 Sep 17.

Authors

Xianjun Dong^{1

2}, Zhixiang Liao^{1

2}, David Gritsch^{1

2}, Yavor Hadzhiev³, Yunfei Bai^{1

4}, Joseph J Locascio^{1

2

5}, Boris Guennewig^{6

7

8}, Ganqiang Liu^{1

2}, Cornelis Blauwendraat⁹, Tao Wang^{1

2}, Charles H Adler¹⁰, John C Hedreen¹¹, Richard L M Faull¹², Matthew P Frosch¹³, Peter T Nelson¹⁴, Patrizia Rizzu⁹, Antony A Cooper^{7

8}, Peter Heutink⁹, Thomas G Beach¹⁵, John S Mattick^{7

8}, Ferenc Müller³, Clemens R Scherzer^{16

17

18

19

20}

Affiliations

¹ Precision Neurology Program, Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA.
² Center for Advanced Parkinson's Disease Research of Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA.
³ Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
⁴ State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
⁵ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Sydney Medical School, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.
⁷ Division of Neuroscience, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
⁸ St Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia.
⁹ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
¹⁰ Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
¹¹ Harvard Brain Tissue Resource Center, McLean Hospital, Harvard Medical School, Boston, MA, USA.
¹² Centre for Brain Research, University of Auckland, Auckland, New Zealand.
¹³ C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
¹⁵ Banner Sun Health Research Institute, Sun City, AZ, USA.
¹⁶ Precision Neurology Program, Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA. [email protected].
¹⁷ Center for Advanced Parkinson's Disease Research of Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA. [email protected].
¹⁸ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. [email protected].
¹⁹ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
²⁰ Program in Neuroscience, Harvard Medical School, Boston, MA, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / pathology*
Dopaminergic Neurons / physiology*
Enhancer Elements, Genetic / genetics
Female
Gene Expression Regulation
Genetic Variation / genetics*
Humans
Male
Mental Disorders / genetics*
Mental Disorders / pathology*
Quantitative Trait Loci / genetics*
Zebrafish

Abstract

Publication types

MeSH terms

Grants and funding