Genome-wide pleiotropy between Parkinson disease and autoimmune diseases

for the International Parkinson's Disease Genomics Consortium (IPDGC), United Kingdom Brain Expression Consortium (UKBEC) Investigators, North American Brain Expression Consortium (NABEC)

Research output: Contribution to journalArticle

40 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 languageEnglish
Pages (from-to)780-792
Number of pages13
JournalJAMA Neurology
Volume74
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017
Externally publishedYes

Fingerprint

Autoimmune Diseases
Parkinson Disease
Genome
Genome-Wide Association Study
Phenotype
Ulcerative Colitis
Crohn Disease
HLA-DRB5 Chains
Rheumatoid Arthritis
Genes
Protein Interaction Maps
Proteins
Immune System Diseases
Celiac Disease
Type 1 Diabetes Mellitus
Psoriasis
Methylation
Multiple Sclerosis
Anti-Inflammatory Agents
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

for the 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, 74(7), 780-792. https://doi.org/10.1001/jamaneurol.2017.0469

Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. / for the International Parkinson's Disease Genomics Consortium (IPDGC), United Kingdom Brain Expression Consortium (UKBEC) Investigators, North American Brain Expression Consortium (NABEC).

In: JAMA Neurology, Vol. 74, No. 7, 01.07.2017, p. 780-792.

Research output: Contribution to journalArticle

for the 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
for the International Parkinson's Disease Genomics Consortium (IPDGC), United Kingdom Brain Expression Consortium (UKBEC) Investigators, North American Brain Expression Consortium (NABEC). Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurology. 2017 Jul 1;74(7):780-792. https://doi.org/10.1001/jamaneurol.2017.0469
for the International Parkinson's Disease Genomics Consortium (IPDGC), United Kingdom Brain Expression Consortium (UKBEC) Investigators, North American Brain Expression Consortium (NABEC). / Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. In: JAMA Neurology. 2017 ; Vol. 74, No. 7. pp. 780-792.
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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.",
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T1 - Genome-wide pleiotropy between Parkinson disease and autoimmune diseases

AU - for the International Parkinson's Disease Genomics Consortium (IPDGC), United Kingdom Brain Expression Consortium (UKBEC) Investigators, North American Brain Expression Consortium (NABEC)

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 - Majounie, Elisa

PY - 2017/7/1

Y1 - 2017/7/1

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.

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