Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases

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 outcome was 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 in methylation 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.

[1]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[2]  A. Ramasamy,et al.  Quality control parameters on a large dataset of regionally dissected human control brains for whole genome expression studies , 2011, Journal of neurochemistry.

[3]  D. Hernandez,et al.  Comprehensive promoter level expression quantitative trait loci analysis of the human frontal lobe , 2016, Genome Medicine.

[4]  C. Kallenberg,et al.  Inflammation in autoimmunity: receptors for IgG revisited. , 2001, Trends in immunology.

[5]  P. Vieregge,et al.  Parkinsonism in multiple sclerosis , 1992, Movement disorders : official journal of the Movement Disorder Society.

[6]  E. Spjøtvoll,et al.  Plots of P-values to evaluate many tests simultaneously , 1982 .

[7]  S. Nisole,et al.  TRIM family proteins: retroviral restriction and antiviral defence , 2005, Nature Reviews Microbiology.

[8]  Helen Schuilenburg,et al.  Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes , 2009, Nature Genetics.

[9]  M. McCarthy,et al.  Genome-wide association studies for complex traits: consensus, uncertainty and challenges , 2008, Nature Reviews Genetics.

[10]  P. Deloukas,et al.  Multiple common variants for celiac disease influencing immune gene expression , 2010, Nature Genetics.

[11]  P. Carvey,et al.  Neuroinflammation and Peripheral Immune Infiltration in Parkinson's Disease: An Autoimmune Hypothesis , 2008, Cell transplantation.

[12]  J. Sundquist,et al.  Subsequent Risks of Parkinson Disease in Patients with Autoimmune and Related Disorders: A Nationwide Epidemiological Study from Sweden , 2011, Neurodegenerative Diseases.

[13]  Nicholas Eriksson,et al.  NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases , 2015, Neurobiology of Aging.

[14]  K. Cheng,et al.  Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders , 2015, Science Signaling.

[15]  S. Factor,et al.  Association of Parkinson disease with structural and regulatory variants in the HLA region. , 2013, American journal of human genetics.

[16]  Zhihua Liu,et al.  The role of LRRK2 in inflammatory bowel disease , 2012, Cell Research.

[17]  M. Frisch,et al.  Multiple sclerosis and risk of Parkinson's disease: a Danish nationwide cohort study , 2014, European journal of neurology.

[18]  Luigi Ferrucci,et al.  Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain , 2010, PLoS genetics.

[19]  C. Moussa,et al.  Inflammation in the early stages of neurodegenerative pathology , 2011, Journal of Neuroimmunology.

[20]  Mark R Cookson,et al.  Distinct DNA methylation changes highly correlated with chronological age in the human brain. , 2011, Human molecular genetics.

[21]  Y Wang,et al.  Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci , 2014, Molecular Psychiatry.

[22]  Xiong Zhang,et al.  The RIT2 and STX1B polymorphisms are associated with Parkinson's disease. , 2015, Parkinsonism & related disorders.

[23]  Jiali Han,et al.  Genetic determinants of hair color and parkinson's disease risk , 2009, Annals of neurology.

[24]  A. Singleton,et al.  Genetic variability in the regulation of gene expression in ten regions of the human brain , 2014, Nature Neuroscience.

[25]  Eric Jacobs,et al.  Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease , 2005, Annals of neurology.

[26]  Christophe Tzourio,et al.  Association between Parkinson's disease and the HLA‐DRB1 locus , 2012, Movement disorders : official journal of the Movement Disorder Society.

[27]  A Smith,et al.  Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus , 2015, Molecular Psychiatry.

[28]  W. Willett,et al.  Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. , 2003, Archives of neurology.

[29]  Chuong B. Do,et al.  Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease , 2014, Nature Genetics.

[30]  H. Heiken,et al.  The IgG Fc receptor family , 1998, Annals of Hematology.

[31]  Christian Gieger,et al.  Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. , 2012, American journal of human genetics.

[32]  D. Hernandez,et al.  A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease. , 2013, Human molecular genetics.

[33]  J. Stow,et al.  SNAREing immunity: the role of SNAREs in the immune system , 2006, Nature Reviews Immunology.

[34]  Mohamad Saad,et al.  Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. , 2013, Human molecular genetics.

[35]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[36]  C. Pellegrini,et al.  Intestinal dysfunction in Parkinson's disease: Lessons learned from translational studies and experimental models , 2016, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[37]  D. Hernandez,et al.  Fine-Mapping, Gene Expression and Splicing Analysis of the Disease Associated LRRK2 Locus , 2013, PloS one.

[38]  Q. Zhang,et al.  Commensal bacteria direct selective cargo sorting to promote symbiosis , 2015, Nature Immunology.

[39]  W. Domschke,et al.  Crucial role of the melanocortin receptor MC1R in experimental colitis , 2006, Gut.

[40]  J. Racoosin,et al.  Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. , 2004, Diabetes care.

[41]  Kasper Lage,et al.  Pervasive Sharing of Genetic Effects in Autoimmune Disease , 2011, PLoS genetics.

[42]  S. Tapscott,et al.  Myotonic dystrophy: emerging mechanisms for DM1 and DM2. , 2007, Biochimica et biophysica acta.

[43]  D. Torpy,et al.  Corticotropin‐Releasing Hormone and Inflammation , 1998, Annals of the New York Academy of Sciences.

[44]  C. Wijmenga,et al.  Association of FcgR2a, but not FcgR3a, with inflammatory bowel diseases across three Caucasian populations† , 2010, Inflammatory bowel diseases.

[45]  Kenneth G. C. Smith,et al.  Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease , 2016, PLoS genetics.

[46]  S. Akira,et al.  Regulation of innate immune signalling pathways by the tripartite motif (TRIM) family proteins , 2011, EMBO molecular medicine.

[47]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[48]  M. Gershon,et al.  The bowel and beyond: the enteric nervous system in neurological disorders , 2016, Nature Reviews Gastroenterology &Hepatology.

[49]  Mohamad Saad,et al.  Genetic comorbidities in Parkinson's disease. , 2014, Human molecular genetics.

[50]  P. Gregersen,et al.  Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes , 2015, European Journal of Human Genetics.

[51]  P. Mcgeer,et al.  Inflammation and neurodegeneration in Parkinson's disease. , 2004, Parkinsonism & related disorders.

[52]  Jing Cui,et al.  Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci , 2010, Nature Genetics.

[53]  Simon C. Potter,et al.  Using genome-wide complex trait analysis to quantify ‘ missing heritability ’ in Parkinson ’ s disease , 2012 .

[54]  Simon C. Potter,et al.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis , 2011, Nature.

[55]  E. Pedemonte,et al.  Parkinsonism in multiple sclerosis patients: a casual or causal association? , 2013, Parkinsonism & related disorders.

[56]  H. Gendelman,et al.  Innate and adaptive immunity for the pathobiology of Parkinson's disease. , 2009, Antioxidants & redox signaling.

[57]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[58]  Judy H. Cho,et al.  Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis , 2013, Nature Genetics.

[59]  J. Olsen,et al.  Autoimmune disease and risk for Parkinson disease , 2009, Neurology.

[60]  Tariq Ahmad,et al.  Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47 , 2011, Nature Genetics.

[61]  O. Andreassen,et al.  Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease. , 2016, JAMA neurology.

[62]  Tariq Ahmad,et al.  Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci , 2010, Nature Genetics.

[63]  V. Perry,et al.  Microglial physiology: unique stimuli, specialized responses. , 2009, Annual review of immunology.

[64]  Y. Mizuno,et al.  Inflammation and infection in Parkinson's disease. , 2006, Histology and histopathology.

[65]  Simon C. Potter,et al.  A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease , 2011, PLoS genetics.

[66]  M. McCarthy,et al.  Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. , 2013, American journal of human genetics.

[67]  E. Sakashita,et al.  Activation of Pre-mRNA Splicing by Human RNPS1 Is Regulated by CK2 Phosphorylation , 2005, Molecular and Cellular Biology.

[68]  Judy H. Cho,et al.  Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease , 2008, Nature Genetics.

[69]  D. Rujescu,et al.  Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate , 2013, PLoS genetics.

[70]  M. Farrer,et al.  Association of the MAPT locus with Parkinson’s disease , 2010, European journal of neurology.

[71]  Mohamad Saad,et al.  Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies , 2011, The Lancet.

[72]  J. Loike,et al.  Neurodegeneration and inflammation in Parkinson's disease. , 2012, Parkinsonism & related disorders.

[73]  Sonja W. Scholz,et al.  Genome-Wide Association Study reveals genetic risk underlying Parkinson’s disease , 2009, Nature Genetics.

[74]  P. Kaliman,et al.  Myotonic dystrophy protein kinase (DMPK) and its role in the pathogenesis of myotonic dystrophy 1. , 2008, Cellular signalling.

[75]  H. Gendelman,et al.  Inflammation and adaptive immunity in Parkinson's disease. , 2012, Cold Spring Harbor perspectives in medicine.

[76]  B. Maček,et al.  PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection. , 2015, Cell host & microbe.

[77]  Isaac Dialsingh,et al.  Large-scale inference: empirical Bayes methods for estimation, testing, and prediction , 2012 .

[78]  D. Clayton,et al.  Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes , 2009, Nature Genetics.