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

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

doi:10.1038/s41593-018-0223-0

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

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Author(s): Xianjun Dong ¹ ^, ² , Zhixiang Liao ¹ ^, ² , David Gritsch ¹ ^, ² , Yavor Hadzhiev ³ , Yunfei Bai ¹ ^, ⁴ , Joseph J Locascio ¹ ^, ² ^, ⁵ , Boris Guennewig ⁶ ^, ⁷ ^, ⁸ , Ganqiang Liu ¹ ^, ² , Cornelis Blauwendraat ⁹ , Tao Wang ¹ ^, ² , Charles H Adler ¹⁰ , John C Hedreen ¹¹ , Richard L M Faull ¹² , Matthew P Frosch ¹³ , Peter T Nelson ¹⁴ , Patrizia Rizzu ⁹ , Antony A Cooper ⁷ ^, ⁸ , Peter Heutink ⁹ , Thomas G Beach ¹⁵ , John S Mattick ⁷ ^, ⁸ , Ferenc Müller ³ , Clemens R Scherzer ¹ ^, ² ^, ⁵ ^, ¹⁶ ^, ¹⁷ ^, ^*

Publication date (Electronic): 17 September 2018

Journal: Nature neuroscience

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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 dis- ease 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.

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Most cited references 34

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Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.

A J Hughes, S Daniel, L Kilford … (1992)

Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.

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DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants

Janet Piñero, Àlex Bravo, Núria Queralt-Rosinach … (2016)

The information about the genetic basis of human diseases lies at the heart of precision medicine and drug discovery. However, to realize its full potential to support these goals, several problems, such as fragmentation, heterogeneity, availability and different conceptualization of the data must be overcome. To provide the community with a resource free of these hurdles, we have developed DisGeNET (http://www.disgenet.org), one of the largest available collections of genes and variants involved in human diseases. DisGeNET integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. DisGeNET data are homogeneously annotated with controlled vocabularies and community-driven ontologies. Additionally, several original metrics are provided to assist the prioritization of genotype–phenotype relationships. The information is accessible through a web interface, a Cytoscape App, an RDF SPARQL endpoint, scripts in several programming languages and an R package. DisGeNET is a versatile platform that can be used for different research purposes including the investigation of the molecular underpinnings of specific human diseases and their comorbidities, the analysis of the properties of disease genes, the generation of hypothesis on drug therapeutic action and drug adverse effects, the validation of computationally predicted disease genes and the evaluation of text-mining methods performance.

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ChIP-seq accurately predicts tissue-specific activity of enhancers.

Axel Visel, Matthew J. Blow, Zirong Li … (2009)

A major yet unresolved quest in decoding the human genome is the identification of the regulatory sequences that control the spatial and temporal expression of genes. Distant-acting transcriptional enhancers are particularly challenging to uncover because they are scattered among the vast non-coding portion of the genome. Evolutionary sequence constraint can facilitate the discovery of enhancers, but fails to predict when and where they are active in vivo. Here we present the results of chromatin immunoprecipitation with the enhancer-associated protein p300 followed by massively parallel sequencing, and map several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain and limb tissue. We tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases demonstrated reproducible enhancer activity in the tissues that were predicted by p300 binding. Our results indicate that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities, and suggest that such data sets will be useful to study the role of tissue-specific enhancers in human biology and disease on a genome-wide scale.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9809671

Journal ID (pubmed-jr-id): 21092

Journal ID (nlm-ta): Nat Neurosci

Journal ID (iso-abbrev): Nat. Neurosci.

Title: Nature neuroscience

ISSN (Print): 1097-6256

ISSN (Electronic): 1546-1726

Publication date Nihms-submitted: 13 September 2018

Publication date (Electronic): 17 September 2018

Publication date (Print): October 2018

Publication date PMC-release: 17 March 2019

Volume: 21

Issue: 10

Pages: 1482-1492

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 Lab for Bioelectroincs, 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, Australia

[7 ]Division of Neuroscience, Garvan Institute of Medical Research, Sydney, NSW, Australia

[8 ]St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, 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 ]Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, MA, USA

[17 ]Program in Neuroscience, Harvard Medical School, Boston, MA, USA

Author notes

Author Contributions

X.D. performed data analysis with important contributions from D.G., B.G., G.L., C.B., and T.W.. T.G.B., C.H.A., M.P.F., P.T.N., J.C.H., R.L.M.F., C.R.S. obtained, and clinically and neuropathologically characterized patient samples. Z.L., D.G. were responsible for laser-capture and RNAseq data production. Z.L., Y.B. performed validation experiments. F.M., Y.H. designed and performed zebrafish experiments. C.B., P.R., P.H. performed CAGE experiments. C.R.S. and X.D. wrote the paper with input from all other authors. C.R.S., J.S.M., F.M., A.A.C., J.J.L. oversaw data analysis, interpretation, and contributed funding. C.R.S. conceived, designed, analyzed, and interpreted the study.

[* ]Correspondence should be addressed to Clemens R Scherzer ( cscherzer@ 123456rics.bwh.harvard.edu )

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Manuscript ID: NIHMS1502311

DOI: 10.1038/s41593-018-0223-0

PMC ID: 6334654

PubMed ID: 30224808

SO-VID: cd516174-5c76-4bcf-bb07-e92dd066475e

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

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Behavioral phenotypization of a mouse model for Alzheimer's: PDAPP = Tg(APPV717F)109Ili

Most cited references 34

Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.

DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants

ChIP-seq accurately predicts tissue-specific activity of enhancers.

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