Genome-wide pleiotropy between Parkinson disease and autoimmune diseases

Aree Witoelar; Iris E. Jansen; Yunpeng Wang; Rahul S. Desikan; J. Raphael Gibbs; Cornelis Blauwendraat; Wesley K. Thompson; Dena G. Hernandez; Srdjan Djurovic; Andrew J. Schork; Francesco Bettella; David Ellinghaus; Andre Franke; Benedicte A. Lie; Linda K. McEvoy; Tom H. Karlsen; Suzanne Lesage; Huw R. Morris; Alexis Brice; Nicholas W. Wood; Peter Heutink; John Hardy; Andrew B. Singleton; Anders M. Dale; Thomas Gasser; Ole A. Andreassen; Manu Sharma; Mike A. Nalls; Vincent Plagnol; Una Marie Sheerin; Mohamad Saad; Javier Simon-Sanchez; Claudia Schulte; Sigurlaug Sveinbjornsdottir; Sampath Arepalli; Roger Barker; Yoav Ben-Shlomo; Henk W. Berendse; Daniela Berg; Kailash Bhatia; Rob M.A. De Bie; Alessandro Biffi; Bas Bloem; Zoltan Bochdanovits; Michael Bonin; Jose M. Bras; Kathrin Brockmann; Janet Brooks; David J. Burn; Carl Counsell; International Parkinson's Disease Genomics Consortium (IPDGC); United Kingdom Brain Expression Consortium (UKBEC) Investigators; North American Brain Expression Consortium (NABEC)

doi:10.1001/jamaneurol.2017.0469

Genome-wide pleiotropy between Parkinson disease and autoimmune diseases

Aree Witoelar, Iris E. Jansen, Yunpeng Wang, Rahul S. Desikan, J. Raphael Gibbs, Cornelis Blauwendraat, Wesley K. Thompson, Dena G. Hernandez, Srdjan Djurovic, Andrew J. Schork, Francesco Bettella, David Ellinghaus, Andre Franke, Benedicte A. Lie, Linda K. McEvoy, Tom H. Karlsen, Suzanne Lesage, Huw R. Morris, Alexis Brice, Nicholas W. WoodPeter Heutink, John Hardy, Andrew B. Singleton, Anders M. Dale, Thomas Gasser, Ole A. Andreassen, Manu Sharma^*, Mike A. Nalls, Vincent Plagnol, Una Marie Sheerin, Mohamad Saad, Javier Simon-Sanchez, Claudia Schulte, Sigurlaug Sveinbjornsdottir, Sampath Arepalli, Roger Barker, Yoav Ben-Shlomo, Henk W. Berendse, Daniela Berg, Kailash Bhatia, Rob M.A. De Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Jose M. Bras, Kathrin Brockmann, Janet Brooks, David J. Burn, Carl Counsell, International Parkinson's Disease Genomics Consortium (IPDGC), United Kingdom Brain Expression Consortium (UKBEC) Investigators, North American Brain Expression Consortium (NABEC)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

215 Citations (Scopus)

Abstract

IMPORTANCE: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. OBJECTIVES: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. DESIGN, SETTING, AND PARTICIPANTS: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. MAIN OUTCOMES AND MEASURES: The primary outcomewas a list of novel loci and their pathways involved in PD and autoimmune diseases. RESULTS: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes inmethylation or expression levels of adjacent genes. CONCLUSIONS AND RELEVANCE: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

Original language	English
Pages (from-to)	780-792
Number of pages	13
Journal	JAMA Neurology
Volume	74
Issue number	7
DOIs	https://doi.org/10.1001/jamaneurol.2017.0469
Publication status	Published - Jul 2017

Bibliographical note

Funding Information:
This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysINFLAME grant 01ZX1306A). This project received infrastructure support from the Deutsche Forschungsgemeinschaft (DFG) Excellence Cluster 306 "Inflammation at Interfaces." Dr Jansen receives funding from Prinses Beatrix Fonds. Dr Franke receives an endowment professorship by the Foundation for Experimental Medicine (Zurich, Switzerland). Dr Andreassen and his team are supported by The Research Council of Norway (213837, 225989, 223273, and 475 237250/EU Joint Programme-Neurodegenerative Disease Research [EU-JPND]), the South East Norway Health Authority (2013-123), the Norwegian Health Association, and the K. G. Jebsen Foundation. Dr Sharma receives funding from The Michael J Fox Foundation for Parkinson's Research and the EU-JPND program (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease [COURAGE-PD]).

UN SDGs

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

Access to Document

10.1001/jamaneurol.2017.0469Licence: Unspecified

Cite this

Witoelar, A., Jansen, I. E., Wang, Y., Desikan, R. S., Gibbs, J. R., Blauwendraat, C., Thompson, W. K., Hernandez, D. G., Djurovic, S., Schork, A. J., Bettella, F., Ellinghaus, D., Franke, A., Lie, B. A., McEvoy, L. K., Karlsen, T. H., Lesage, S., Morris, H. R., Brice, A., ... North American Brain Expression Consortium (NABEC) (2017). Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurology, 74(7), 780-792. https://doi.org/10.1001/jamaneurol.2017.0469

Witoelar, A, Jansen, IE, Wang, Y, Desikan, RS, Gibbs, JR, Blauwendraat, C, Thompson, WK, Hernandez, DG, Djurovic, S, Schork, AJ, Bettella, F, Ellinghaus, D, Franke, A, Lie, BA, McEvoy, LK, Karlsen, TH, Lesage, S, Morris, HR, Brice, A, Wood, NW, Heutink, P, Hardy, J, Singleton, AB, Dale, AM, Gasser, T, Andreassen, OA, Sharma, M, Nalls, MA, Plagnol, V, Sheerin, UM, Saad, M, Simon-Sanchez, J, Schulte, C, Sveinbjornsdottir, S, Arepalli, S, Barker, R, Ben-Shlomo, Y, Berendse, HW, Berg, D, Bhatia, K, De Bie, RMA, Biffi, A, Bloem, B, Bochdanovits, Z, Bonin, M, Bras, JM, Brockmann, K, Brooks, J, Burn, DJ, Counsell, C, International Parkinson's Disease Genomics Consortium (IPDGC), United Kingdom Brain Expression Consortium (UKBEC) Investigators & North American Brain Expression Consortium (NABEC) 2017, 'Genome-wide pleiotropy between Parkinson disease and autoimmune diseases', JAMA Neurology, vol. 74, no. 7, pp. 780-792. https://doi.org/10.1001/jamaneurol.2017.0469

@article{b36681e6c70749c1aa8c69f6b6e50f9c,

title = "Genome-wide pleiotropy between Parkinson disease and autoimmune diseases",

abstract = "IMPORTANCE: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. OBJECTIVES: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. DESIGN, SETTING, AND PARTICIPANTS: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. MAIN OUTCOMES AND MEASURES: The primary outcomewas a list of novel loci and their pathways involved in PD and autoimmune diseases. RESULTS: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes inmethylation or expression levels of adjacent genes. CONCLUSIONS AND RELEVANCE: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.",

author = "Aree Witoelar and Jansen, {Iris E.} and Yunpeng Wang and Desikan, {Rahul S.} and Gibbs, {J. Raphael} and Cornelis Blauwendraat and Thompson, {Wesley K.} and Hernandez, {Dena G.} and Srdjan Djurovic and Schork, {Andrew J.} and Francesco Bettella and David Ellinghaus and Andre Franke and Lie, {Benedicte A.} and McEvoy, {Linda K.} and Karlsen, {Tom H.} and Suzanne Lesage and Morris, {Huw R.} and Alexis Brice and Wood, {Nicholas W.} and Peter Heutink and John Hardy and Singleton, {Andrew B.} and Dale, {Anders M.} and Thomas Gasser and Andreassen, {Ole A.} and Manu Sharma and Nalls, {Mike A.} and Vincent Plagnol and Sheerin, {Una Marie} and Mohamad Saad and Javier Simon-Sanchez and Claudia Schulte and Sigurlaug Sveinbjornsdottir and Sampath Arepalli and Roger Barker and Yoav Ben-Shlomo and Berendse, {Henk W.} and Daniela Berg and Kailash Bhatia and {De Bie}, {Rob M.A.} and Alessandro Biffi and Bas Bloem and Zoltan Bochdanovits and Michael Bonin and Bras, {Jose M.} and Kathrin Brockmann and Janet Brooks and Burn, {David J.} and Carl Counsell and {International Parkinson's Disease Genomics Consortium (IPDGC)} and {United Kingdom Brain Expression Consortium (UKBEC) Investigators} and {North American Brain Expression Consortium (NABEC)}",

note = "Funding Information: This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysINFLAME grant 01ZX1306A). This project received infrastructure support from the Deutsche Forschungsgemeinschaft (DFG) Excellence Cluster 306 {"}Inflammation at Interfaces.{"} Dr Jansen receives funding from Prinses Beatrix Fonds. Dr Franke receives an endowment professorship by the Foundation for Experimental Medicine (Zurich, Switzerland). Dr Andreassen and his team are supported by The Research Council of Norway (213837, 225989, 223273, and 475 237250/EU Joint Programme-Neurodegenerative Disease Research [EU-JPND]), the South East Norway Health Authority (2013-123), the Norwegian Health Association, and the K. G. Jebsen Foundation. Dr Sharma receives funding from The Michael J Fox Foundation for Parkinson's Research and the EU-JPND program (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease [COURAGE-PD]). ",

year = "2017",

month = jul,

doi = "10.1001/jamaneurol.2017.0469",

language = "English",

volume = "74",

pages = "780--792",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "7",

}

TY - JOUR

T1 - Genome-wide pleiotropy between Parkinson disease and autoimmune diseases

AU - Witoelar, Aree

AU - Jansen, Iris E.

AU - Wang, Yunpeng

AU - Desikan, Rahul S.

AU - Gibbs, J. Raphael

AU - Blauwendraat, Cornelis

AU - Thompson, Wesley K.

AU - Hernandez, Dena G.

AU - Djurovic, Srdjan

AU - Schork, Andrew J.

AU - Bettella, Francesco

AU - Ellinghaus, David

AU - Franke, Andre

AU - Lie, Benedicte A.

AU - McEvoy, Linda K.

AU - Karlsen, Tom H.

AU - Lesage, Suzanne

AU - Morris, Huw R.

AU - Brice, Alexis

AU - Wood, Nicholas W.

AU - Heutink, Peter

AU - Hardy, John

AU - Singleton, Andrew B.

AU - Dale, Anders M.

AU - Gasser, Thomas

AU - Andreassen, Ole A.

AU - Sharma, Manu

AU - Nalls, Mike A.

AU - Plagnol, Vincent

AU - Sheerin, Una Marie

AU - Saad, Mohamad

AU - Simon-Sanchez, Javier

AU - Schulte, Claudia

AU - Sveinbjornsdottir, Sigurlaug

AU - Arepalli, Sampath

AU - Barker, Roger

AU - Ben-Shlomo, Yoav

AU - Berendse, Henk W.

AU - Berg, Daniela

AU - Bhatia, Kailash

AU - De Bie, Rob M.A.

AU - Biffi, Alessandro

AU - Bloem, Bas

AU - Bochdanovits, Zoltan

AU - Bonin, Michael

AU - Bras, Jose M.

AU - Brockmann, Kathrin

AU - Brooks, Janet

AU - Burn, David J.

AU - Counsell, Carl

AU - International Parkinson's Disease Genomics Consortium (IPDGC)

AU - United Kingdom Brain Expression Consortium (UKBEC) Investigators

AU - North American Brain Expression Consortium (NABEC)

N1 - Funding Information: This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysINFLAME grant 01ZX1306A). This project received infrastructure support from the Deutsche Forschungsgemeinschaft (DFG) Excellence Cluster 306 "Inflammation at Interfaces." Dr Jansen receives funding from Prinses Beatrix Fonds. Dr Franke receives an endowment professorship by the Foundation for Experimental Medicine (Zurich, Switzerland). Dr Andreassen and his team are supported by The Research Council of Norway (213837, 225989, 223273, and 475 237250/EU Joint Programme-Neurodegenerative Disease Research [EU-JPND]), the South East Norway Health Authority (2013-123), the Norwegian Health Association, and the K. G. Jebsen Foundation. Dr Sharma receives funding from The Michael J Fox Foundation for Parkinson's Research and the EU-JPND program (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease [COURAGE-PD]).

PY - 2017/7

Y1 - 2017/7

N2 - IMPORTANCE: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. OBJECTIVES: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. DESIGN, SETTING, AND PARTICIPANTS: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. MAIN OUTCOMES AND MEASURES: The primary outcomewas a list of novel loci and their pathways involved in PD and autoimmune diseases. RESULTS: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes inmethylation or expression levels of adjacent genes. CONCLUSIONS AND RELEVANCE: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

AB - IMPORTANCE: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. OBJECTIVES: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. DESIGN, SETTING, AND PARTICIPANTS: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. MAIN OUTCOMES AND MEASURES: The primary outcomewas a list of novel loci and their pathways involved in PD and autoimmune diseases. RESULTS: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes inmethylation or expression levels of adjacent genes. CONCLUSIONS AND RELEVANCE: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

UR - http://www.scopus.com/inward/record.url?scp=85024384526&partnerID=8YFLogxK

U2 - 10.1001/jamaneurol.2017.0469

DO - 10.1001/jamaneurol.2017.0469

M3 - Article

C2 - 28586827

AN - SCOPUS:85024384526

SN - 2168-6149

VL - 74

SP - 780

EP - 792

JO - JAMA Neurology

JF - JAMA Neurology

IS - 7

ER -

Genome-wide pleiotropy between Parkinson disease and autoimmune diseases

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this