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1. Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis

Author

Mirkov, Maša Umiċeviċ, Cui, Jing, Vermeulen, Sita H, Stahl, Eli A, Toonen, Erik JM, Makkinje, Remco R, Lee, Annette T, Huizinga, Tom WJ, Allaart, Renee, Barton, Anne, Mariette, Xavier, Miceli, Corinne Richard, Criswell, Lindsey A, Tak, Paul P, de Vries, Niek, Saevarsdottir, Saedis, Padyukov, Leonid, Bridges, S Louis, van Schaardenburg, Dirk-Jan, Jansen, Tim L, Dutmer, Ellen AJ, van de Laar, Mart AFJ, Barrera, Pilar, Radstake, Timothy RDJ, van Riel, Piet LCM, Scheffer, Hans, Franke, Barbara, Brunner, Han G, Plenge, Robert M, Gregersen, Peter K, Guchelaar, Henk-Jan, and Coenen, Marieke JH

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Arthritis, Rheumatoid Arthritis, Genetics, Autoimmune Disease, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Adalimumab, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antirheumatic Agents, Arthritis, Rheumatoid, DNA Mutational Analysis, Drug Resistance, Etanercept, Female, Gene Expression Regulation, Genetic Markers, Genome-Wide Association Study, Humans, Immunoglobulin G, Infliximab, Male, Polymorphism, Single Nucleotide, Receptors, Tumor Necrosis Factor, Registries, Tumor Necrosis Factor-alpha, Anti-TNF, Gene Polymorphism, Pharmacogenetics, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

BackgroundTreatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach.MethodsWe conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p

Published
2013

2. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

Author

Gorlova, Olga, Martin, Jose-Ezequiel, Rueda, Blanca, Koeleman, Bobby PC, Ying, Jun, Teruel, Maria, Diaz-Gallo, Lina-Marcela, Broen, Jasper C, Vonk, Madelon C, Simeon, Carmen P, Alizadeh, Behrooz Z, Coenen, Marieke JH, Voskuyl, Alexandre E, Schuerwegh, Annemie J, van Riel, Piet LCM, Vanthuyne, Marie, van 't Slot, Ruben, Italiaander, Annet, Ophoff, Roel A, Hunzelmann, Nicolas, Fonollosa, Vicente, Ortego-Centeno, Norberto, González-Gay, Miguel A, García-Hernández, Francisco J, González-Escribano, María F, Airo, Paolo, van Laar, Jacob, Worthington, Jane, Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul G, Westhovens, Rene, Kreuter, Alexander, de Baere, Elfride, Witte, Torsten, Padyukov, Leonid, Nordin, Annika, Scorza, Raffaella, Lunardi, Claudio, Lie, Benedicte A, Hoffmann-Vold, Anna-Maria, Palm, Oyvind, García de la Peña, Paloma, Carreira, Patricia, Spanish Scleroderma Group, Varga, John, Hinchcliff, Monique, Lee, Annette T, Gourh, Pravitt, Amos, Christopher I, Wigley, Frederick M, Hummers, Laura K, Nelson, J Lee, Riemekasten, Gabriella, Herrick, Ariane, Beretta, Lorenzo, Fonseca, Carmen, Denton, Christopher P, Gregersen, Peter K, Agarwal, Sandeep, Assassi, Shervin, Tan, Filemon K, Arnett, Frank C, Radstake, Timothy RDJ, Mayes, Maureen D, and Martin, Javier

Subjects
Spanish Scleroderma Group, Humans, Scleroderma, Systemic, Genetic Predisposition to Disease, Genetic Markers, Autoantibodies, HLA Antigens, Phenotype, Polymorphism, Single Nucleotide, Alleles, Middle Aged, Female, Male, Genome-Wide Association Study, Genetic Loci, Polymorphism, Single Nucleotide, Scleroderma, Systemic, Genetics, Developmental Biology
Abstract

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84×10(-21), OR = 0.55) and ATA (P = 1.14×10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

Published
2011

5. Evaluating the Frequencies of CNOT3, GRIA1, NFATC2, and PNPLA3 Variant Alleles and Their Association with L-Asparaginase Hypersensitivity in Pediatric Acute Lymphoblastic Leukemia in Addis Ababa, Ethiopia

Author

Ali,Awol Mekonnen, Adam,Haileyesus, Hailu,Daniel, Howe,Rawleigh, Abula,Teferra, Coenen,Marieke JH, Ali,Awol Mekonnen, Adam,Haileyesus, Hailu,Daniel, Howe,Rawleigh, Abula,Teferra, and Coenen,Marieke JH

Abstract

Awol Mekonnen Ali,1 Haileyesus Adam,2 Daniel Hailu,2 Rawleigh Howe,3 Teferra Abula,1 Marieke JH Coenen4 1Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 2Department of Pediatrics and Child Health, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 3Armauer Hansen Research Institute, Addis Ababa, Ethiopia; 4Department of Human Genetics, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the NetherlandsCorrespondence: Awol Mekonnen Ali, Addis Ababa, Ethiopia, Tel +251 913914432, Email awolalim@gmail.comIntroduction: L-asparaginase is a vital component for the treatment of childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions and hepatotoxicity hinder its anti-neoplastic efficacy. Previous reports indicated that genetic variants in CNOT3, GRIA1, and NFATC2 genes might be associated with hypersensitivity reactions and PNPLA3 with liver function.Objective: In this study, it was investigated whether this association also exists in a pediatric ALL cohort from Ethiopia.Methods: Three variants GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were genotyped in a cohort of 160 patients. Association analysis to investigate the association with hypersensitivity reactions was performed using logistic regression analyses. Besides these variants, a variant in PNPLA3 (rs738409) was genotyped to assess the association with liver function.Results: Genotype frequencies of GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were higher/lower than previously reported. One hundred and forty-four patients were included in the association analysis of which, 18 (12.5%) developed L-ASP hypersensitivity. Though the frequency of hypersensitivity was higher in patients that carried the risk alleles of the three investigated genes, no statistically significant differences were observed.

Published
2023

6. Potential added value of combined DPYD/DPD genotyping and phenotyping to prevent severe toxicity in patients with a DPYD variant and decreased dihydropyrimidine dehydrogenase enzyme activity.

Author

Ockeloen, Charlotte W, Raaijmakers, Aron, Hijmans-van der Vegt, Manon, Bierau, Jörgen, de Vos-Geelen, Judith, Willemsen, Annelieke ECAB, van den Bosch, Bianca JC, and Coenen, Marieke JH

Subjects
ENZYME metabolism, PHARMACOGENOMICS, GENETIC polymorphisms, RETROSPECTIVE studies, FLUOROURACIL, COLORECTAL cancer, ANTIMETABOLITES, GENOTYPES, ENZYMES, DRUG therapy, BIOLOGICAL assay, PHENOTYPES, DRUG toxicity, LONGITUDINAL method, PATIENT safety
Abstract

Decreased dihydropyrimidine dehydrogenase enzyme activity is associated with severe fluoropyrimidine-associated toxicity. Four clinically relevant variants in the DPYD gene are associated with decreased dihydropyrimidine dehydrogenase activity. However, only ∼25% of DPYD variant carriers show a decreased dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells. Objective: To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD genotyping in predicting fluoropyrimidine-related toxicity. Methods: Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay. Results: Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities. Conclusions: Our results indicate that a combined genotype–phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort. [ABSTRACT FROM AUTHOR]

Published
2023
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7. Potential added value of combined DPYD/DPD genotyping and phenotyping to prevent severe toxicity in patients with a DPYD variant and decreased dihydropyrimidine dehydrogenase enzyme activity

Author

Ockeloen, Charlotte W, primary, Raaijmakers, Aron, additional, Hijmans-van der Vegt, Manon, additional, Bierau, Jörgen, additional, de Vos-Geelen, Judith, additional, Willemsen, Annelieke ECAB, additional, van den Bosch, Bianca JC, additional, and Coenen, Marieke JH, additional

Published
2021
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9. sj-docx-1-opp-10.1177_10781552211049144 - Supplemental material for Potential added value of combined DPYD/DPD genotyping and phenotyping to prevent severe toxicity in patients with a DPYD variant and decreased dihydropyrimidine dehydrogenase enzyme activity

Author

Ockeloen, Charlotte W, Raaijmakers, Aron, Hijmans-van der Vegt, Manon, Bierau, J��rgen, de Vos-Geelen, Judith, Willemsen, Annelieke ECAB, van den Bosch, Bianca JC, and Coenen, Marieke JH

Subjects
FOS: Clinical medicine, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 111299 Oncology and Carcinogenesis not elsewhere classified
Abstract

Supplemental material, sj-docx-1-opp-10.1177_10781552211049144 for Potential added value of combined DPYD/DPD genotyping and phenotyping to prevent severe toxicity in patients with a DPYD variant and decreased dihydropyrimidine dehydrogenase enzyme activity by Charlotte W Ockeloen, Aron Raaijmakers, Manon Hijmans-van der Vegt, J��rgen Bierau, Judith de Vos-Geelen, Annelieke ECAB Willemsen, Bianca JC van den Bosch and Marieke JH Coenen in Journal of Oncology Pharmacy Practice

Published
2021
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14. Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39

Author

Spiliopoulou, Athina, primary, Colombo, Marco, additional, Plant, Darren, additional, Nair, Nisha, additional, Cui, Jing, additional, Coenen, Marieke JH, additional, Ikari, Katsunori, additional, Yamanaka, Hisashi, additional, Saevarsdottir, Saedis, additional, Padyukov, Leonid, additional, Bridges Jr., S Louis, additional, Kimberly, Robert P, additional, Okada, Yukinori, additional, van Riel, Piet L CM, additional, Wolbink, Gertjan, additional, van der Horst-Bruinsma, Irene E, additional, de Vries, Niek, additional, Tak, Paul P, additional, Ohmura, Koichiro, additional, Canhão, Helena, additional, Guchelaar, Henk-Jan, additional, Huizinga, Tom WJ, additional, Criswell, Lindsey A, additional, Raychaudhuri, Soumya, additional, Weinblatt, Michael E, additional, Wilson, Anthony G, additional, Mariette, Xavier, additional, Isaacs, John D, additional, Morgan, Ann W, additional, Pitzalis, Costantino, additional, Barton, Anne, additional, and McKeigue, Paul, additional

Published
2019
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15. Survival dimensionality reduction (SDR): development and clinical application of an innovative approach to detect epistasis in presence of right-censored data

Author

Beretta Lorenzo, Santaniello Alessandro, van Riel Piet LCM, Coenen Marieke JH, and Scorza Raffaella

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR) algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets. Results The algorithm requires neither specification about the underlying survival distribution nor about the underlying interaction model and proved satisfactorily powerful to detect a set of causative genes in synthetic epistatic lifetime datasets with a limited number of samples and high degree of right-censorship (up to 70%). The SDR method was then applied to a series of 386 Dutch patients with active rheumatoid arthritis that were treated with anti-TNF biological agents. Among a set of 39 candidate genes, none of which showed a detectable marginal effect on anti-TNF responses, the SDR algorithm did find that the rs1801274 SNP in the FcγRIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals. Conclusions Simulation studies and application in a real-world setting support the capability of the SDR algorithm to model epistatic interactions in candidate-genes studies in presence of right-censored data. Availability: http://sourceforge.net/projects/sdrproject/

Published
2010
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16. The role of rare protein-coding variants to anti-TNF treatment response in rheumatoid arthritis

Author

Cui, Jing, Diogo, Dorothee, Stahl, Eli A, Canhao, Helena, Mariette, Xavier, Greenberg, Jeffrey D, Okada, Yukinori, Pappas, Dimitrios A, Fulton, Robert S, Tak, Paul P, Nurmohamed, Michael T, Lee, Annette, Larson, David E, Kurreeman, Fina, Deluca, Tracie L, O'Laughlin, Michelle, Fronick, Catrina C, Fulton, Lucinda L, Mardis, Elaine R, van der Horst-Bruinsma, Irene E, Wolbink, Gert-Jan, Gregersen, Peter K, Kremer, Joel M, Crusius, J Bart A, de Vries, Niek, Huizinga, Tom W J, Fonseca, João Eurico, Miceli-Richard, Corinne, Karlson, Elizabeth W, Coenen, Marieke Jh, Barton, Anne, Plenge, Robert M, Raychaudhuri, Soumya, AII - Inflammatory diseases, Rheumatology, and ICaR - Circulation and metabolism

Abstract

Objective Many rheumatoid arthritis (RA) patients have their disease controlled with anti-tumor necrosis factor alpha (anti-TNF) biologic therapies. However, a significant number of RA patients fail to respond to anti-TNF therapy. Here, we hypothesized that rare and low-frequency variants might influence anti-TNF treatment response. Methods We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry treated with anti-TNF medications. After quality control, we included 690 genes in the analysis. We applied single variants association and gene-based association tests to identify variants associated with anti-TNF treatment response. We also performed gene set analyses of 27 TNF pathway genes, considering TNF's key mechanistic role. Results We identified 14,420 functional variants, of which 6,934 were predicted as non-synonymous where 2,136 were further predicted to be damaging. Despite being a well-powered study, no single variant or gene showed study-wide significant association with change in disease activity outcome or EULAR response outcome. Intriguingly, we observed 3 genes, out of 27 with nominal signals of association (P

Published
2017
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18. Pharmacogenetics of inflammatory bowel disease

Author

van den Bosch, Bianca JC and Coenen, Marieke JH

Abstract

Patients with inflammatory bowel disease (IBD) show large variability in disease course, and also treatment response. The variability in treatment response has led to many initiatives in search of genetic markers to optimize treatment and avoid severe side effects. This has been very successful for thiopurines, one of the drugs used to induce and maintain remission in IBD. However, for the newer treatment options for IBD, like biologicals, the search for genetic predictors has not yielded any candidate biomarkers with clinical utility. In this review, a summary of recent advances in pharmacogenetics focusing on thiopurines and anti-TNF agents is given.

Published
2020
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19. New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis

Author

Lee, S Hong, Byrne, Enda M., Hultman, Christina M., Kähler, Anna, Vinkhuyzen, Anna AE, Ripke, Stephan, Andreassen, Ole A., Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X., McGrath, John J., Mehta, Divya, Stahl, Eli A., Zhao, Qiongyi, Kendler, Kenneth S., Sullivan, Patrick F., Price, Alkes L., O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J., Raychaudhuri, Soumya, Wray, Naomi R., Byerley, William, Cahn, Wiepke, Cantor, Rita M., Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V., Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F., Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H., McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W., Nöthen, Markus M., O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N., Pato, Michele T., Pickard, Benjamin S., Posthuma, Danielle, Rasmussen, Henrik B., Rietschel, Marcella, Rujescu, Dan, Schulze, Thomas G., Silverman, Jeremy M., Thirumalai, Srinivasa, Werge, Thomas, Agartz, Ingrid, Amin, Farooq, Azevedo, Maria H., Bass, Nicholas, Black, Donald W., Blackwood, Douglas H R., Bruggeman, Richard, Buccola, Nancy G., Choudhury, Khalid, Cloninger, Robert C., Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Datta, Susmita, Donohoe, Gary J., Duan, Jubao, Dudbridge, Frank, Fanous, Ayman, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Gill, Michael, Gurling, Hugh, De Haan, Lieuwe, Hamshere, Marian L., Hartmann, Annette M., Holmans, Peter A., Kahn, René S., Keller, Matthew C., Kenny, Elaine, Kirov, George K., Krabbendam, Lydia, Krasucki, Robert, Lawrence, Jacob, Lencz, Todd, Levinson, Douglas F., Lieberman, Jeffrey A., Lin, Dan-Yu, Linszen, Don H., Magnusson, Patrik KE, Maier, Wolfgang, Malhotra, Anil K., Mattheisen, Manuel, Mattingsdal, Morten, McCarroll, Steven A., Medeiros, Helena, Melle, Ingrid, Milanova, Vihra, Myin-Germeys, Inez, Neale, Benjamin M., Ophoff, Roel A., Owen, Michael J., Pimm, Jonathan, Purcell, Shaun M., Puri, Vinay, Quested, Digby J., Rossin, Lizzy, Ruderfer, Douglas, Sanders, Alan R., Shi, Jianxin, Sklar, Pamela, St. Clair, David, Stroup, T Scott, Van Os, Jim, Visscher, Peter M., Wiersma, Durk, Zammit, Stanley, Bridges, S Louis, Choi, Hyon K., Coenen, Marieke JH, de Vries, Niek, Dieud, Philippe, Greenberg, Jeffrey D., Huizinga, Tom WJ, Padyukov, Leonid, Siminovitch, Katherine A., Tak, Paul P., Worthington, Jane, De Jager, Philip L., Denny, Joshua C., Gregersen, Peter K., Klareskog, Lars, Mariette, Xavier, Plenge, Robert M., van Laar, Mart, van Riel, Piet, Lee, S Hong, Byrne, Enda M., Hultman, Christina M., Kähler, Anna, Vinkhuyzen, Anna AE, Ripke, Stephan, Andreassen, Ole A., Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X., McGrath, John J., Mehta, Divya, Stahl, Eli A., Zhao, Qiongyi, Kendler, Kenneth S., Sullivan, Patrick F., Price, Alkes L., O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J., Raychaudhuri, Soumya, Wray, Naomi R., Byerley, William, Cahn, Wiepke, Cantor, Rita M., Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V., Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F., Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H., McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W., Nöthen, Markus M., O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N., Pato, Michele T., Pickard, Benjamin S., Posthuma, Danielle, Rasmussen, Henrik B., Rietschel, Marcella, Rujescu, Dan, Schulze, Thomas G., Silverman, Jeremy M., Thirumalai, Srinivasa, Werge, Thomas, Agartz, Ingrid, Amin, Farooq, Azevedo, Maria H., Bass, Nicholas, Black, Donald W., Blackwood, Douglas H R., Bruggeman, Richard, Buccola, Nancy G., Choudhury, Khalid, Cloninger, Robert C., Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Datta, Susmita, Donohoe, Gary J., Duan, Jubao, Dudbridge, Frank, Fanous, Ayman, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Gill, Michael, Gurling, Hugh, De Haan, Lieuwe, Hamshere, Marian L., Hartmann, Annette M., Holmans, Peter A., Kahn, René S., Keller, Matthew C., Kenny, Elaine, Kirov, George K., Krabbendam, Lydia, Krasucki, Robert, Lawrence, Jacob, Lencz, Todd, Levinson, Douglas F., Lieberman, Jeffrey A., Lin, Dan-Yu, Linszen, Don H., Magnusson, Patrik KE, Maier, Wolfgang, Malhotra, Anil K., Mattheisen, Manuel, Mattingsdal, Morten, McCarroll, Steven A., Medeiros, Helena, Melle, Ingrid, Milanova, Vihra, Myin-Germeys, Inez, Neale, Benjamin M., Ophoff, Roel A., Owen, Michael J., Pimm, Jonathan, Purcell, Shaun M., Puri, Vinay, Quested, Digby J., Rossin, Lizzy, Ruderfer, Douglas, Sanders, Alan R., Shi, Jianxin, Sklar, Pamela, St. Clair, David, Stroup, T Scott, Van Os, Jim, Visscher, Peter M., Wiersma, Durk, Zammit, Stanley, Bridges, S Louis, Choi, Hyon K., Coenen, Marieke JH, de Vries, Niek, Dieud, Philippe, Greenberg, Jeffrey D., Huizinga, Tom WJ, Padyukov, Leonid, Siminovitch, Katherine A., Tak, Paul P., Worthington, Jane, De Jager, Philip L., Denny, Joshua C., Gregersen, Peter K., Klareskog, Lars, Mariette, Xavier, Plenge, Robert M., van Laar, Mart, and van Riel, Piet

Abstract

Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (−0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (−0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090). Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context

Published
2017

20. Genetics of rheumatoid arthritis contributes to biology and drug discovery

Author

Okada, Yukinori, Wu, Di, Trynka, Gosia, Raj, Towfique, Terao, Chikashi, Ikari, Katsunori, Kochi, Yuta, Ohmura, Koichiro, Suzuki, Akari, Yoshida, Shinji, Graham, Robert R, Manoharan, Arun, Ortmann, Ward, Bhangale, Tushar, Denny, Joshua C, Carroll, Robert J, Eyler, Anne E, Greenberg, Jeffrey D, Kremer, Joel M, Pappas, Dimitrios A, Jiang, Lei, Yin, Jian, Ye, Lingying, Su, Ding-Feng, Yang, Jian, Xie, Gang, Keystone, Ed, Westra, Harm-Jan, Esko, Tonu, Metspalu, Andres, Zhou, Xuezhong, Gupta, Namrata, Mirel, Daniel, Stahl, Eli A, Diogo, Dorothee, Cui, Jing, Liao, Katherine, Guo, Michael H, Myouzen, Keiko, Kawaguchi, Takahisa, Coenen, Marieke JH, van Riel, Piet LCM, van de laar, Mart AFJ, Guchelaar, Henk-Jan, Huizinga, Tom WJ, Dieude, Philippe, Mariette, Xavier, Bridges, S Louis, Jr., Zhernakova, Alexandra, Toes, Rene EM, Tak, Paul P, Miceli-Richard, Corinne, Bang, So-Young, Lee, Hye-Soon, Martin, Javier, Gonzalez-Gay, Miguel A, Rodriguez-Rodriguez, Luis, Rantapää-Dahlqvist, Solbritt, Ärlestig, Lisbeth, Choi, Hyon K, Kamatani, Yoichiro, Galan, Pilar, Lathrop, Mark, Eyre, Steve, Bowes, John, Barton, Anne, de Vries, Niek, Moreland, Larry W, Criswell, Lindsey A, Karlson, Elizabeth W, Taniguchi, Atsuo, Yamada, Ryo, Kubo, Michiaki, Liu, Jun S, Bae, Sang-Cheol, Worthington, Jane, Padyukov, Leonid, Klareskog, Lars, Gregersen, Peter K, Raychaudhuri, Soumya, Stranger, Barbara E, De Jager, Philip L, Franke, Lude, Visscher, Peter M, Brown, Matthew A, Yamanaka, Hisashi, Mimori, Tsuneyo, Takahashi, Atsushi, Xu, Huji, Behrens, Timothy W, Siminovitch, Katherine A, Momohara, Shigeki, Matsuda, Fumihiko, Yamamoto, Kazuhiko, Plenge, Robert M, Okada, Yukinori, Wu, Di, Trynka, Gosia, Raj, Towfique, Terao, Chikashi, Ikari, Katsunori, Kochi, Yuta, Ohmura, Koichiro, Suzuki, Akari, Yoshida, Shinji, Graham, Robert R, Manoharan, Arun, Ortmann, Ward, Bhangale, Tushar, Denny, Joshua C, Carroll, Robert J, Eyler, Anne E, Greenberg, Jeffrey D, Kremer, Joel M, Pappas, Dimitrios A, Jiang, Lei, Yin, Jian, Ye, Lingying, Su, Ding-Feng, Yang, Jian, Xie, Gang, Keystone, Ed, Westra, Harm-Jan, Esko, Tonu, Metspalu, Andres, Zhou, Xuezhong, Gupta, Namrata, Mirel, Daniel, Stahl, Eli A, Diogo, Dorothee, Cui, Jing, Liao, Katherine, Guo, Michael H, Myouzen, Keiko, Kawaguchi, Takahisa, Coenen, Marieke JH, van Riel, Piet LCM, van de laar, Mart AFJ, Guchelaar, Henk-Jan, Huizinga, Tom WJ, Dieude, Philippe, Mariette, Xavier, Bridges, S Louis, Jr., Zhernakova, Alexandra, Toes, Rene EM, Tak, Paul P, Miceli-Richard, Corinne, Bang, So-Young, Lee, Hye-Soon, Martin, Javier, Gonzalez-Gay, Miguel A, Rodriguez-Rodriguez, Luis, Rantapää-Dahlqvist, Solbritt, Ärlestig, Lisbeth, Choi, Hyon K, Kamatani, Yoichiro, Galan, Pilar, Lathrop, Mark, Eyre, Steve, Bowes, John, Barton, Anne, de Vries, Niek, Moreland, Larry W, Criswell, Lindsey A, Karlson, Elizabeth W, Taniguchi, Atsuo, Yamada, Ryo, Kubo, Michiaki, Liu, Jun S, Bae, Sang-Cheol, Worthington, Jane, Padyukov, Leonid, Klareskog, Lars, Gregersen, Peter K, Raychaudhuri, Soumya, Stranger, Barbara E, De Jager, Philip L, Franke, Lude, Visscher, Peter M, Brown, Matthew A, Yamanaka, Hisashi, Mimori, Tsuneyo, Takahashi, Atsushi, Xu, Huji, Behrens, Timothy W, Siminovitch, Katherine A, Momohara, Shigeki, Matsuda, Fumihiko, Yamamoto, Kazuhiko, and Plenge, Robert M

Abstract

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Published
2014
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21. Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis.

Author

Umiċeviċ Mirkov, Maša, Umiċeviċ Mirkov, Maša, Cui, Jing, Vermeulen, Sita H, Stahl, Eli A, Toonen, Erik JM, Makkinje, Remco R, Lee, Annette T, Huizinga, Tom WJ, Allaart, Renee, Barton, Anne, Mariette, Xavier, Miceli, Corinne Richard, Criswell, Lindsey A, Tak, Paul P, de Vries, Niek, Saevarsdottir, Saedis, Padyukov, Leonid, Bridges, S Louis, van Schaardenburg, Dirk-Jan, Jansen, Tim L, Dutmer, Ellen AJ, van de Laar, Mart AFJ, Barrera, Pilar, Radstake, Timothy RDJ, van Riel, Piet LCM, Scheffer, Hans, Franke, Barbara, Brunner, Han G, Plenge, Robert M, Gregersen, Peter K, Guchelaar, Henk-Jan, Coenen, Marieke JH, Umiċeviċ Mirkov, Maša, Umiċeviċ Mirkov, Maša, Cui, Jing, Vermeulen, Sita H, Stahl, Eli A, Toonen, Erik JM, Makkinje, Remco R, Lee, Annette T, Huizinga, Tom WJ, Allaart, Renee, Barton, Anne, Mariette, Xavier, Miceli, Corinne Richard, Criswell, Lindsey A, Tak, Paul P, de Vries, Niek, Saevarsdottir, Saedis, Padyukov, Leonid, Bridges, S Louis, van Schaardenburg, Dirk-Jan, Jansen, Tim L, Dutmer, Ellen AJ, van de Laar, Mart AFJ, Barrera, Pilar, Radstake, Timothy RDJ, van Riel, Piet LCM, Scheffer, Hans, Franke, Barbara, Brunner, Han G, Plenge, Robert M, Gregersen, Peter K, Guchelaar, Henk-Jan, and Coenen, Marieke JH

Abstract

BackgroundTreatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach.MethodsWe conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10(-3) were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10(-3) was performed using Ingenuity.Results772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology.ConclusionsUsing a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.

Published
2013

23. Meta-analysis identified the TNFA -308G > A promoter polymorphism as a risk factor for disease severity in patients with rheumatoid arthritis

Author

Toonen, Erik JM, primary, Barrera, Pilar, additional, Fransen, Jaap, additional, de Brouwer, Arjan PM, additional, Eijsbouts, Agnes M, additional, Miossec, Pierre, additional, Marotte, Hubert, additional, Scheffer, Hans, additional, van Riel, Piet LCM, additional, Franke, Barbara, additional, and Coenen, Marieke JH, additional

Published
2012
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24. A rare polymorphism in Toll Like Receptor 2 is associated with systemic sclerosis phenotype and increases production of inflammatory mediators

Author

Broen, Jasper CA, primary, Bossini-Castillo, Lara, additional, Bon, Lenny van, additional, Vonk, Madelon C, additional, Knaapen, Hanneke, additional, Beretta, Lorenzo, additional, Rueda, Blanca, additional, Hesselstrand, Roger, additional, Herrick, Ariane, additional, Worthington, Jane, additional, Hunzelmann, Nicholas, additional, Denton, Christopher, additional, Fonseca, Carmen, additional, Riemekasten, Gabriela, additional, Kiener, Hans, additional, Scorza, Raffaella, additional, Simeon, Carmen P, additional, Ortego-Centeno, Norberto, additional, Gonzalez-Gay, Miguel A, additional, Airo’, Paolo, additional, Coenen, Marieke JH, additional, Martin, Javier, additional, and Radstake, Timothy RDJ, additional

Published
2011
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26. A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

Author

De Boer, Elke, Ockeloen, Charlotte W, Matalonga, Leslie, Horvath, Rita, Solve-RD SNV-Indel Working Group, Rodenburg, Richard J, Coenen, Marieke JH, Janssen, Mirian, Henssen, Dylan, Gilissen, Christian, Steyaert, Wouter, Paramonov, Ida, Solve-RD-DITF-ITHACA, Trimouille, Aurélien, Kleefstra, Tjitske, Verloes, Alain, and Vissers, Lisenka ELM

Subjects
Male, Young Adult, Epilepsy, RNA, Transfer, Leu, Intellectual Disability, Mutation, Exome Sequencing, Humans, Quadriplegia, 3. Good health
Abstract

Funder: The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257, The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.

27. New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis

Author

Lee, S Hong, Byrne, Enda M., Hultman, Christina M., Kähler, Anna, Vinkhuyzen, Anna AE, Ripke, Stephan, Andreassen, Ole A., Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X., McGrath, John J., Mehta, Divya, Stahl, Eli A., Zhao, Qiongyi, Kendler, Kenneth S., Sullivan, Patrick F., Price, Alkes L., O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J., Raychaudhuri, Soumya, Wray, Naomi R., Byerley, William, Cahn, Wiepke, Cantor, Rita M., Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V., Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F., Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H., McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W., Nöthen, Markus M., O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N., Pato, Michele T., Pickard, Benjamin S., Posthuma, Danielle, Rasmussen, Henrik B., Rietschel, Marcella, Rujescu, Dan, Schulze, Thomas G., Silverman, Jeremy M., Thirumalai, Srinivasa, Werge, Thomas, Agartz, Ingrid, Amin, Farooq, Azevedo, Maria H., Bass, Nicholas, Black, Donald W., Blackwood, Douglas H R., Bruggeman, Richard, Buccola, Nancy G., Choudhury, Khalid, Cloninger, Robert C., Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Datta, Susmita, Donohoe, Gary J., Duan, Jubao, Dudbridge, Frank, Fanous, Ayman, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Gill, Michael, Gurling, Hugh, De Haan, Lieuwe, Hamshere, Marian L., Hartmann, Annette M., Holmans, Peter A., Kahn, René S., Keller, Matthew C., Kenny, Elaine, Kirov, George K., Krabbendam, Lydia, Krasucki, Robert, Lawrence, Jacob, Lencz, Todd, Levinson, Douglas F., Lieberman, Jeffrey A., Lin, Dan-Yu, Linszen, Don H., Magnusson, Patrik KE, Maier, Wolfgang, Malhotra, Anil K., Mattheisen, Manuel, Mattingsdal, Morten, McCarroll, Steven A., Medeiros, Helena, Melle, Ingrid, Milanova, Vihra, Myin-Germeys, Inez, Neale, Benjamin M., Ophoff, Roel A., Owen, Michael J., Pimm, Jonathan, Purcell, Shaun M., Puri, Vinay, Quested, Digby J., Rossin, Lizzy, Ruderfer, Douglas, Sanders, Alan R., Shi, Jianxin, Sklar, Pamela, St. Clair, David, Stroup, T Scott, Van Os, Jim, Visscher, Peter M., Wiersma, Durk, Zammit, Stanley, Bridges, S Louis, Choi, Hyon K., Coenen, Marieke JH, de Vries, Niek, Dieud, Philippe, Greenberg, Jeffrey D., Huizinga, Tom WJ, Padyukov, Leonid, Siminovitch, Katherine A., Tak, Paul P., Worthington, Jane, De Jager, Philip L., Denny, Joshua C., Gregersen, Peter K., Klareskog, Lars, Mariette, Xavier, Plenge, Robert M., van Laar, Mart, van Riel, Piet, Lee, S Hong, Byrne, Enda M., Hultman, Christina M., Kähler, Anna, Vinkhuyzen, Anna AE, Ripke, Stephan, Andreassen, Ole A., Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X., McGrath, John J., Mehta, Divya, Stahl, Eli A., Zhao, Qiongyi, Kendler, Kenneth S., Sullivan, Patrick F., Price, Alkes L., O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J., Raychaudhuri, Soumya, Wray, Naomi R., Byerley, William, Cahn, Wiepke, Cantor, Rita M., Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V., Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F., Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H., McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W., Nöthen, Markus M., O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N., Pato, Michele T., Pickard, Benjamin S., Posthuma, Danielle, Rasmussen, Henrik B., Rietschel, Marcella, Rujescu, Dan, Schulze, Thomas G., Silverman, Jeremy M., Thirumalai, Srinivasa, Werge, Thomas, Agartz, Ingrid, Amin, Farooq, Azevedo, Maria H., Bass, Nicholas, Black, Donald W., Blackwood, Douglas H R., Bruggeman, Richard, Buccola, Nancy G., Choudhury, Khalid, Cloninger, Robert C., Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Datta, Susmita, Donohoe, Gary J., Duan, Jubao, Dudbridge, Frank, Fanous, Ayman, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Gill, Michael, Gurling, Hugh, De Haan, Lieuwe, Hamshere, Marian L., Hartmann, Annette M., Holmans, Peter A., Kahn, René S., Keller, Matthew C., Kenny, Elaine, Kirov, George K., Krabbendam, Lydia, Krasucki, Robert, Lawrence, Jacob, Lencz, Todd, Levinson, Douglas F., Lieberman, Jeffrey A., Lin, Dan-Yu, Linszen, Don H., Magnusson, Patrik KE, Maier, Wolfgang, Malhotra, Anil K., Mattheisen, Manuel, Mattingsdal, Morten, McCarroll, Steven A., Medeiros, Helena, Melle, Ingrid, Milanova, Vihra, Myin-Germeys, Inez, Neale, Benjamin M., Ophoff, Roel A., Owen, Michael J., Pimm, Jonathan, Purcell, Shaun M., Puri, Vinay, Quested, Digby J., Rossin, Lizzy, Ruderfer, Douglas, Sanders, Alan R., Shi, Jianxin, Sklar, Pamela, St. Clair, David, Stroup, T Scott, Van Os, Jim, Visscher, Peter M., Wiersma, Durk, Zammit, Stanley, Bridges, S Louis, Choi, Hyon K., Coenen, Marieke JH, de Vries, Niek, Dieud, Philippe, Greenberg, Jeffrey D., Huizinga, Tom WJ, Padyukov, Leonid, Siminovitch, Katherine A., Tak, Paul P., Worthington, Jane, De Jager, Philip L., Denny, Joshua C., Gregersen, Peter K., Klareskog, Lars, Mariette, Xavier, Plenge, Robert M., van Laar, Mart, and van Riel, Piet

Abstract

Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (−0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (−0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090). Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context

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