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

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 journal › Article › peer-review

44 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 language	English
Pages (from-to)	1482-1492
Number of pages	11
Journal	Nature Neuroscience
Volume	21
Issue number	10
DOIs	https://doi.org/10.1038/s41593-018-0223-0
State	Published - Oct 1 2018

Bibliographical note

Funding Information:
We thank H. Suzuki and T. Suzuki of RIKEN for providing the modified pGL4.10_mod3_EF1α vector and consultation. We are grateful to C. Vanderburg of the Advanced Tissue Resource Center, Massachusetts General Hospital, for his expertise and support. We thank Z. Weng at the University of Massachusetts Medical School for sharing additional data from the ENCODE consortium. We thank A. Sandelin and R. Andersson, both from Copenhagen University; A. Regev, Broad Institute; and M. Feany, Brigham & Women's Hospital, for insightful comments and guidance. We thank C. Liu, A. Shieh, and T. Goodman for assisting in extracting the RNA-seq and ATAC-seq data in the BrainGVEX dataset. We gratefully acknowledge the Banner Sun Health Institute, Massachusetts Alzheimer’s Disease Research Center at Massachusetts General Hospital, Harvard Brain Tissue Resource Center at McLean Hospital, University of Kentucky ADC Tissue Bank, University of Maryland Brain and Tissue Bank, Pacific Northwest Dementia and Aging Neuropathology Group at University of Washington Medicine Center, and Neurological Foundation of New Zealand for providing human brain tissue. This study was funded in part by NIH grant U01 NS082157 and the US Department of Defense (to C.R.S.); NIH R01AG057331 (to C.R.S.) funded RNA-seq of pyramidal neurons; with additional support from the Michael J. Fox Foundation (MJFF) (to C.R.S. and C.H.A., respectively); the Australia NHMRC GNT1067350 (to A.A.C. and J.S.M.); NIA P30 AG028383 (to P.T.N.); UK Wellcome Trust Investigator award (to F.M.); NINDS U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders (to T.G.B. and C.H.A.); NIA P50 AG005134 (to M.P.F.). The MSBB data were generated as part of the AMP-AD Consortium from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by E. Schadt from Mount Sinai School of Medicine. PsychENCODE data were generated as part of the PsychENCODE Consortium, supported by grants U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877, and P50MH106934 awarded to S. Akbarian (Icahn School of Medicine at Mount Sinai), G. Crawford (Duke), S. Dracheva (Icahn School of Medicine at Mount Sinai), P. Farnham (USC), M. Gerstein (Yale), D. Geschwind (UCLA), T.M. Hyde (LIBD), A. Jaffe (LIBD), J.A. Knowles (USC), C. Liu (UIC), D. Pinto (Icahn School of Medicine at Mount Sinai), N. Sestan (Yale), P. Sklar (Icahn School of Medicine at Mount Sinai), M. State (UCSF), P. Sullivan (UNC), F. Vaccarino (Yale), S. Weissman (Yale), K. White (U Chicago), and P. Zandi (JHU).

Funding Information:
C.R.S. has collaborated with Pfizer and Sanofi; has consulted for Sanofi; has served as Advisor to the Michael J. Fox Foundation, NIH, and Department of Defense; is on the Scientific Advisory Board of the American Parkinson Disease Association; received funding from the NIH, the US Department of Defense, the Michael J. Fox Foundation, and the American Parkinson Disease Association; and is named as co-inventor on two US patent applications on biomarkers for PD held in part by Brigham & Women’s Hospital. B.G. is the founder of Pacific Analytics PTY LTD, Australia and is a founding member of the International Cerebral Palsy Genetics Consortium, a member of the Australian Genomics Health Alliance, and is on the Scientific Advisory Board of Iggy Get Out!, Australia. T.G.B. provides consultancies to Prothena and GSK; is on the Advisory Board of Vivid Genomics; and has contracted research with Avid Radiopharmaceuticals, Navidea Biopharmaceuticals, and Aprinoia Therapeutics. The other authors declare no competing financial interests.

Funding Information:
Human cortex TNEs supported by ATAC-seq peaks

Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

Neuroscience (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41593-018-0223-0

Cite this

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

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title = "Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease",

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{\textquoteright}s disease were enriched in these elements. Expression quantitative trait locus analysis revealed that Parkinson{\textquoteright}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.",

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

note = "Funding Information: We thank H. Suzuki and T. Suzuki of RIKEN for providing the modified pGL4.10_mod3_EF1α vector and consultation. We are grateful to C. Vanderburg of the Advanced Tissue Resource Center, Massachusetts General Hospital, for his expertise and support. We thank Z. Weng at the University of Massachusetts Medical School for sharing additional data from the ENCODE consortium. We thank A. Sandelin and R. Andersson, both from Copenhagen University; A. Regev, Broad Institute; and M. Feany, Brigham & Women's Hospital, for insightful comments and guidance. We thank C. Liu, A. Shieh, and T. Goodman for assisting in extracting the RNA-seq and ATAC-seq data in the BrainGVEX dataset. We gratefully acknowledge the Banner Sun Health Institute, Massachusetts Alzheimer{\textquoteright}s Disease Research Center at Massachusetts General Hospital, Harvard Brain Tissue Resource Center at McLean Hospital, University of Kentucky ADC Tissue Bank, University of Maryland Brain and Tissue Bank, Pacific Northwest Dementia and Aging Neuropathology Group at University of Washington Medicine Center, and Neurological Foundation of New Zealand for providing human brain tissue. This study was funded in part by NIH grant U01 NS082157 and the US Department of Defense (to C.R.S.); NIH R01AG057331 (to C.R.S.) funded RNA-seq of pyramidal neurons; with additional support from the Michael J. Fox Foundation (MJFF) (to C.R.S. and C.H.A., respectively); the Australia NHMRC GNT1067350 (to A.A.C. and J.S.M.); NIA P30 AG028383 (to P.T.N.); UK Wellcome Trust Investigator award (to F.M.); NINDS U24 NS072026 National Brain and Tissue Resource for Parkinson{\textquoteright}s Disease and Related Disorders (to T.G.B. and C.H.A.); NIA P50 AG005134 (to M.P.F.). The MSBB data were generated as part of the AMP-AD Consortium from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by E. Schadt from Mount Sinai School of Medicine. PsychENCODE data were generated as part of the PsychENCODE Consortium, supported by grants U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877, and P50MH106934 awarded to S. Akbarian (Icahn School of Medicine at Mount Sinai), G. Crawford (Duke), S. Dracheva (Icahn School of Medicine at Mount Sinai), P. Farnham (USC), M. Gerstein (Yale), D. Geschwind (UCLA), T.M. Hyde (LIBD), A. Jaffe (LIBD), J.A. Knowles (USC), C. Liu (UIC), D. Pinto (Icahn School of Medicine at Mount Sinai), N. Sestan (Yale), P. Sklar (Icahn School of Medicine at Mount Sinai), M. State (UCSF), P. Sullivan (UNC), F. Vaccarino (Yale), S. Weissman (Yale), K. White (U Chicago), and P. Zandi (JHU). Funding Information: C.R.S. has collaborated with Pfizer and Sanofi; has consulted for Sanofi; has served as Advisor to the Michael J. Fox Foundation, NIH, and Department of Defense; is on the Scientific Advisory Board of the American Parkinson Disease Association; received funding from the NIH, the US Department of Defense, the Michael J. Fox Foundation, and the American Parkinson Disease Association; and is named as co-inventor on two US patent applications on biomarkers for PD held in part by Brigham & Women{\textquoteright}s Hospital. B.G. is the founder of Pacific Analytics PTY LTD, Australia and is a founding member of the International Cerebral Palsy Genetics Consortium, a member of the Australian Genomics Health Alliance, and is on the Scientific Advisory Board of Iggy Get Out!, Australia. T.G.B. provides consultancies to Prothena and GSK; is on the Advisory Board of Vivid Genomics; and has contracted research with Avid Radiopharmaceuticals, Navidea Biopharmaceuticals, and Aprinoia Therapeutics. The other authors declare no competing financial interests. Funding Information: Human cortex TNEs supported by ATAC-seq peaks Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2018",

month = oct,

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doi = "10.1038/s41593-018-0223-0",

language = "English",

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Dong, X, Liao, Z, Gritsch, D, Hadzhiev, Y, Bai, Y, Locascio, JJ, Guennewig, B, Liu, G, Blauwendraat, C, Wang, T, Adler, CH, Hedreen, JC, Faull, RLM, Frosch, MP, Nelson, PT, Rizzu, P, Cooper, AA, Heutink, P, Beach, TG, Mattick, JS, Müller, F & Scherzer, CR 2018, 'Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease', Nature Neuroscience, vol. 21, no. 10, pp. 1482-1492. https://doi.org/10.1038/s41593-018-0223-0

TY - JOUR

T1 - Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease

AU - Dong, Xianjun

AU - Liao, Zhixiang

AU - Gritsch, David

AU - Hadzhiev, Yavor

AU - Bai, Yunfei

AU - Locascio, Joseph J.

AU - Guennewig, Boris

AU - Liu, Ganqiang

AU - Blauwendraat, Cornelis

AU - Wang, Tao

AU - Adler, Charles H.

AU - Hedreen, John C.

AU - Faull, Richard L.M.

AU - Frosch, Matthew P.

AU - Nelson, Peter T.

AU - Rizzu, Patrizia

AU - Cooper, Antony A.

AU - Heutink, Peter

AU - Beach, Thomas G.

AU - Mattick, John S.

AU - Müller, Ferenc

AU - Scherzer, Clemens R.

N1 - Funding Information: We thank H. Suzuki and T. Suzuki of RIKEN for providing the modified pGL4.10_mod3_EF1α vector and consultation. We are grateful to C. Vanderburg of the Advanced Tissue Resource Center, Massachusetts General Hospital, for his expertise and support. We thank Z. Weng at the University of Massachusetts Medical School for sharing additional data from the ENCODE consortium. We thank A. Sandelin and R. Andersson, both from Copenhagen University; A. Regev, Broad Institute; and M. Feany, Brigham & Women's Hospital, for insightful comments and guidance. We thank C. Liu, A. Shieh, and T. Goodman for assisting in extracting the RNA-seq and ATAC-seq data in the BrainGVEX dataset. We gratefully acknowledge the Banner Sun Health Institute, Massachusetts Alzheimer’s Disease Research Center at Massachusetts General Hospital, Harvard Brain Tissue Resource Center at McLean Hospital, University of Kentucky ADC Tissue Bank, University of Maryland Brain and Tissue Bank, Pacific Northwest Dementia and Aging Neuropathology Group at University of Washington Medicine Center, and Neurological Foundation of New Zealand for providing human brain tissue. This study was funded in part by NIH grant U01 NS082157 and the US Department of Defense (to C.R.S.); NIH R01AG057331 (to C.R.S.) funded RNA-seq of pyramidal neurons; with additional support from the Michael J. Fox Foundation (MJFF) (to C.R.S. and C.H.A., respectively); the Australia NHMRC GNT1067350 (to A.A.C. and J.S.M.); NIA P30 AG028383 (to P.T.N.); UK Wellcome Trust Investigator award (to F.M.); NINDS U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders (to T.G.B. and C.H.A.); NIA P50 AG005134 (to M.P.F.). The MSBB data were generated as part of the AMP-AD Consortium from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by E. Schadt from Mount Sinai School of Medicine. PsychENCODE data were generated as part of the PsychENCODE Consortium, supported by grants U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877, and P50MH106934 awarded to S. Akbarian (Icahn School of Medicine at Mount Sinai), G. Crawford (Duke), S. Dracheva (Icahn School of Medicine at Mount Sinai), P. Farnham (USC), M. Gerstein (Yale), D. Geschwind (UCLA), T.M. Hyde (LIBD), A. Jaffe (LIBD), J.A. Knowles (USC), C. Liu (UIC), D. Pinto (Icahn School of Medicine at Mount Sinai), N. Sestan (Yale), P. Sklar (Icahn School of Medicine at Mount Sinai), M. State (UCSF), P. Sullivan (UNC), F. Vaccarino (Yale), S. Weissman (Yale), K. White (U Chicago), and P. Zandi (JHU). Funding Information: C.R.S. has collaborated with Pfizer and Sanofi; has consulted for Sanofi; has served as Advisor to the Michael J. Fox Foundation, NIH, and Department of Defense; is on the Scientific Advisory Board of the American Parkinson Disease Association; received funding from the NIH, the US Department of Defense, the Michael J. Fox Foundation, and the American Parkinson Disease Association; and is named as co-inventor on two US patent applications on biomarkers for PD held in part by Brigham & Women’s Hospital. B.G. is the founder of Pacific Analytics PTY LTD, Australia and is a founding member of the International Cerebral Palsy Genetics Consortium, a member of the Australian Genomics Health Alliance, and is on the Scientific Advisory Board of Iggy Get Out!, Australia. T.G.B. provides consultancies to Prothena and GSK; is on the Advisory Board of Vivid Genomics; and has contracted research with Avid Radiopharmaceuticals, Navidea Biopharmaceuticals, and Aprinoia Therapeutics. The other authors declare no competing financial interests. Funding Information: Human cortex TNEs supported by ATAC-seq peaks Publisher Copyright: © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

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SP - 1482

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ER -

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

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Bibliographical note

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UN SDGs

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