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1. Cell Specific eQTL Analysis without Sorting Cells.

Author

Harm-Jan Westra, Danny Arends, Tõnu Esko, Marjolein J Peters, Claudia Schurmann, Katharina Schramm, Johannes Kettunen, Hanieh Yaghootkar, Benjamin P Fairfax, Anand Kumar Andiappan, Yang Li, Jingyuan Fu, Juha Karjalainen, Mathieu Platteel, Marijn Visschedijk, Rinse K Weersma, Silva Kasela, Lili Milani, Liina Tserel, Pärt Peterson, Eva Reinmaa, Albert Hofman, André G Uitterlinden, Fernando Rivadeneira, Georg Homuth, Astrid Petersmann, Roberto Lorbeer, Holger Prokisch, Thomas Meitinger, Christian Herder, Michael Roden, Harald Grallert, Samuli Ripatti, Markus Perola, Andrew R Wood, David Melzer, Luigi Ferrucci, Andrew B Singleton, Dena G Hernandez, Julian C Knight, Rossella Melchiotti, Bernett Lee, Michael Poidinger, Francesca Zolezzi, Anis Larbi, De Yun Wang, Leonard H van den Berg, Jan H Veldink, Olaf Rotzschke, Seiko Makino, Veikko Salomaa, Konstantin Strauch, Uwe Völker, Joyce B J van Meurs, Andres Metspalu, Cisca Wijmenga, Ritsert C Jansen, and Lude Franke

Subjects
Genetics, QH426-470
Abstract

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.

Published
2015
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2. Correction: Susceptibility to chronic mucus hypersecretion, a genome wide association study.

Author

Akkelies E Dijkstra, Joanna Smolonska, Maarten van den Berge, Ciska Wijmenga, Pieter Zanen, Marjan A Luinge, Mathieu Platteel, Jan-Willem Lammers, Magnus Dahlback, Kerrie Tosh, Pieter S Hiemstra, Peter J Sterk, Avi Spira, Jorgen Vestbo, Borge G Nordestgaard, Marianne Benn, Sune F Nielsen, Morten Dahl, W Monique Verschuren, H Susan J Picavet, Henriette A Smit, Michael Owsijewitsch, Hans U Kauczor, Harry J de Koning, Eva Nizankowska-Mogilnicka, Filip Mejza, Pawel Nastalek, Cleo C van Diemen, Michael H Cho, Edwin K Silverman, James D Crapo, Terri H Beaty, David A Lomas, Per Bakke, Amund Gulsvik, Yohan Bossé, Ma'en Obeidat, Daan W Loth, Lies Lahousse, Fernando Rivadeneira, Andre G Uitterlinden, Andre Hofman, Bruno H Stricker, Guy G Brusselle, Cornelia M van Duijn, Uilke Brouwer, Gerard H Koppelman, Judith M Vonk, Martijn C Nawijn, Harry J M Groen, Wim Timens, H Marike Boezen, Dirkje S Postma, and LifeLines Cohort Study

Subjects
Medicine, Science
Published
2015
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3. Susceptibility to chronic mucus hypersecretion, a genome wide association study.

Author

Akkelies E Dijkstra, Joanna Smolonska, Maarten van den Berge, Ciska Wijmenga, Pieter Zanen, Marjan A Luinge, Mathieu Platteel, Jan-Willem Lammers, Magnus Dahlback, Kerrie Tosh, Pieter S Hiemstra, Peter J Sterk, Avi Spira, Jorgen Vestbo, Borge G Nordestgaard, Marianne Benn, Sune F Nielsen, Morten Dahl, W Monique Verschuren, H Susan J Picavet, Henriette A Smit, Michael Owsijewitsch, Hans U Kauczor, Harry J de Koning, Eva Nizankowska-Mogilnicka, Filip Mejza, Pawel Nastalek, Cleo C van Diemen, Michael H Cho, Edwin K Silverman, James D Crapo, Terri H Beaty, David A Lomas, Per Bakke, Amund Gulsvik, Yohan Bossé, Ma'en Obeidat, Daan W Loth, Lies Lahousse, Fernando Rivadeneira, Andre G Uitterlinden, Andre Hofman, Bruno H Stricker, Guy G Brusselle, Cornelia M van Duijn, Uilke Brouwer, Gerard H Koppelman, Judith M Vonk, Martijn C Nawijn, Harry J M Groen, Wim Timens, H Marike Boezen, Dirkje S Postma, and LifeLines Cohort study

Subjects
Medicine, Science
Abstract

Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations.GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP).A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10(-9)) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture.Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

Published
2014
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4. Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA.

Author

Rudolf S N Fehrmann, Ritsert C Jansen, Jan H Veldink, Harm-Jan Westra, Danny Arends, Marc Jan Bonder, Jingyuan Fu, Patrick Deelen, Harry J M Groen, Asia Smolonska, Rinse K Weersma, Robert M W Hofstra, Wim A Buurman, Sander Rensen, Marcel G M Wolfs, Mathieu Platteel, Alexandra Zhernakova, Clara C Elbers, Eleanora M Festen, Gosia Trynka, Marten H Hofker, Christiaan G J Saris, Roel A Ophoff, Leonard H van den Berg, David A van Heel, Cisca Wijmenga, Gerard J Te Meerman, and Lude Franke

Subjects
Genetics, QH426-470
Abstract

For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological intervention. Here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals. We looked at 1,167 published trait- or disease-associated SNPs and observed trans-eQTL effects on 113 different genes, of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose, visceral adipose, liver tissue, and muscle tissue. HLA single-nucleotide polymorphisms (SNPs) were 10-fold enriched for trans-eQTLs: 48% of the trans-acting SNPs map within the HLA, including ulcerative colitis susceptibility variants that affect plausible candidate genes AOAH and TRBV18 in trans. We identified 18 pairs of unlinked SNPs associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected, P

Published
2011
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5. Immunochip meta-analysis in European and Argentinian populations identifies two novel genetic loci associated with celiac disease

Author

Vinod Kumar, Edgardo Smecuol, Alexander Kurilshikov, Mathieu Platteel, Patrick Deelen, Jingyuan Fu, Oscar Daffra, Serena Sanna, Adriaan van der Graaf, Ana F. Costa, Gosia Trynka, Isis Ricaño-Ponce, Julio C. Bai, Javier Gutierrez-Achury, Sonia I. Niveloni, Cisca Wijmenga, Alexandra Zhernakova, Maria M. Zorro, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
EXPRESSION, SUSCEPTIBILITY LOCI, Chromosomes, Human, Pair 22, NF-KAPPA-B, Argentina, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Genomics, Locus (genetics), Genome-wide association study, Human leukocyte antigen, Disease, Biology, Polymorphism, Single Nucleotide, Article, ACTIVATION, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Lymphotoxin beta Receptor, Genetics, RISK VARIANTS, Guanine Nucleotide Exchange Factors, Humans, Intestinal Mucosa, GENOME-WIDE ASSOCIATION, MULTIPLE COMMON, Gene, Genetics (clinical), 0303 health sciences, Chromosomes, Human, Pair 12, INTERFERON-GAMMA, Tumor Necrosis Factor-alpha, 030305 genetics & heredity, NF-kappa B, NADPH Oxidases, LYMPHOTOXIN-BETA-RECEPTOR, rac GTP-Binding Proteins, Europe, Celiac Disease, Genetic Loci, Meta-analysis, Signal transduction, Cell Adhesion Molecules, Genome-Wide Association Study, RAC2
Abstract

Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4125 additional Caucasian samples including an Argentinian cohort. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations at loci: 12p13.31 and 22q13.1. By applying a genomics approach and differential expression analysis in CeD intestinal biopsies, we prioritize potential causal genes at these novel loci, including LTBR, CYTH4, and RAC2. Nineteen prioritized causal genes are overlapping known drug targets. Pathway enrichment analysis and expression of these genes in CeD biopsies suggest that they have roles in regulating multiple pathways such as the tumor necrosis factor (TNF) mediated signaling pathway and positive regulation of I-κB kinase/NF-κB signaling.

Published
2020
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6. Understanding human immune function using the resources from the Human Functional Genomics Project

Author

Leo A. B. Joosten, Frank L. van de Veerdonk, Bart Jan Kullberg, Jacqueline van der Graaf, Rob ter Horst, Mihai G. Netea, Quirijn de Mast, Marije Oosting, Cisca Wijmenga, Richard A. Notebaart, André J. A. M. van der Ven, Wouter van de Heijden, Rahajeng N. Tunjungputri, Melanie Schirmer, Hera Vlamakis, Inge van de Munckhof, Kiki Schraa, Hans J. P. M. Koenen, Jan Smit, Lude Franke, Curtis Huttenhouwer, Alexandra Zhernakova, Jingyuan Fu, Marten H. Hofker, Mathieu Platteel, Eric A. Franzosa, Joost H.W. Rutten, Ramnik J. Xavier, Astrid Maatman, Kara G. Lassen, Iris Jonkers, Yang Li, Vinod Kumar, Sanne P. Smeekens, Morris A. Swertz, Raul Aguirre-Gamboa, Jos W. M. van der Meer, Norman Pavelka, Aylwin Ng, Cees J. Tack, Romana T. Netea-Maier, Martin Jaeger, Charles A. Dinarello, Daniel B. Graham, Irma Joosten, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP), Translational Immunology Groningen (TRIGR), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
0301 basic medicine, animal diseases, Systems biology, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], chemical and pharmacologic phenomena, Genomics, General Medicine, Computational biology, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], biochemical phenomena, metabolism, and nutrition, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030104 developmental biology, Immune system, Immune System, Human Genome Project, Life Science, Humans, bacteria, Functional genomics, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Abstract

Understanding human immune function using the resources from the Human Functional Genomics Project

Published
2016
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7. Multiple common variants for celiac disease influencing immune gene expression

Author

Anna Rybak, Luigi Greco, Joseph A. Murray, Graham A. Heap, Katherine I. Morley, Maria Teresa Bardella, Päivi Saavalainen, Graham Turner, Jeffrey C. Barrett, Alexandra Zhernakova, Veikko Salomaa, Bárbara Dema, Róza Ádány, Lude Franke, Charles A. Mein, Owen T. McCann, Sarah E. Hunt, Roel A. Ophoff, Susan L. Neuhausen, Rudolf S N Fehrmann, Karen A. Hunt, Patrick Dubois, Kalle Kurppa, Roderick H. J. Houwen, Bożena Cukrowska, Nicholas A. Bockett, M. Luisa Mearin, Leena Peltonen, Elena Urcelay, Emilio G. de la Concha, Maria Cristina Mazzilli, Vanisha Mistry, Rinse K. Weersma, Concepción Núñez, Ross McManus, Harry J.M. Groen, Joachim J. Schweizer, Cisca Wijmenga, Gosia Trynka, Greetje J. Tack, Markku Mäki, Alessandra Curtotti, Rhian Gwilliam, Padraic MacMathuna, Maria Pia Sperandeo, Peter M. Green, David A. van Heel, Jihane Romanos, Dermot Kelleher, Ilma Rita Korponay-Szabó, Victorien M. Wolters, Isabel Polanco, Katri Kaukinen, Szilvia Fiatal, Elvira Grandone, Wieke H. M. Verbeek, Arpo Aromaa, Panos Deloukas, Leonard H. van den Berg, Elvira Oosterom, Barbara Mora, Donatella Barisani, Muddassar M. Mirza, Jan H. Veldink, Mathieu Platteel, Chris J. J. Mulder, Miguel Fernández-Arquero, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Gastroenterology and hepatology, CCA - Immuno-pathogenesis, Dubois, P, Trynka, G, Franke, L, Hunt, K, Romanos, J, Curtotti, A, Zhernakova, A, Heap, G, Adány, R, Aromaa, A, Bardella, M, van den Berg, L, Bockett, N, de la Concha, E, Dema, B, Fehrmann, R, Fernández Arquero, M, Fiatal, S, Grandone, E, Green, P, Groen, H, Gwilliam, R, Houwen, R, Hunt, S, Kaukinen, K, Kelleher, D, Korponay Szabo, I, Kurppa, K, Macmathuna, P, Mäki, M, Mazzilli, M, Mccann, O, Mearin, M, Mein, C, Mirza, M, Mistry, V, Mora, B, Morley, K, Mulder, C, Murray, J, Núñez, C, Oosterom, E, Ophoff, R, Polanco, I, Peltonen, L, Platteel, M, Rybak, A, Salomaa, V, Schweizer, J, Sperandeo, M, Tack, G, Turner, G, Veldink, J, Verbeek, W, Weersma, R, Wolters, V, Urcelay, E, Cukrowska, B, Greco, L, Neuhausen, S, Mcmanus, R, Barisani, D, Deloukas, P, Barrett, J, Saavalainen, P, Wijmenga, C, and van Heel, D

Subjects
POSITIVE SELECTION, HETERODIMER, Genes, MHC Class I, Gene Expression, Genome-wide association study, Medical and Health Sciences, MHC Class I, 0302 clinical medicine, Immunopathology, RISK VARIANTS, 2.1 Biological and endogenous factors, Aetiology, POPULATION, Genetics, 0303 health sciences, education.field_of_study, THYMUS, Orvostudományok, Single Nucleotide, THYMOCYTES, Biological Sciences, 3. Good health, 030220 oncology & carcinogenesis, Egészségtudományok, Human, Biotechnology, Risk, SUSCEPTIBILITY LOCI, Population, Single-nucleotide polymorphism, CLEC16A, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Meta-Analysis as Topic, Humans, Allele, GENOME-WIDE ASSOCIATION, Polymorphism, education, 030304 developmental biology, Gene Expression Profiling, Human Genome, BIO/13 - BIOLOGIA APPLICATA, ALLELES, RHEUMATOID-ARTHRITIS, Gene expression profiling, Celiac Disease, Genes, Case-Control Studies, genome-wide association rheumatoid-arthritis susceptibility loci positive selection risk variants population alleles thymus heterodimer thymocytes, Digestive Diseases, Genome-Wide Association Study, Developmental Biology
Abstract

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS)

Published
2010
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8. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappa B signalling

Author

Donatella Barisani, Chris J. J. Mulder, Graham A. Heap, M.L. Mearin, Jihane Romanos, Cisca Wijmenga, Fiona M. Stevens, Gosia Trynka, Marcel Bruinenberg, David S Sanders, Graham Turner, Peter D. Howdle, Valerie Trimble, D A van Heel, Lude Franke, Wieke H. M. Verbeek, Dermot Kelleher, Alexandra Zhernakova, C. G. F. de Kovel, Karen A. Hunt, Geoffrey Holmes, Ross McManus, Julian R.F. Walters, Anthony W. Ryan, Maria Teresa Bardella, Mathieu Platteel, University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Gastroenterology and hepatology, Other Research, Trynka, G, Zhernakova, A, Romanos, J, Franke, L, Hunt, K, Turner, G, Bruinenberg, M, Heap, G, Platteel, M, Ryan, A, de Kovel, C, Holmes, G, Howdle, P, Walters, J, Sanders, D, Mulder, C, Mearin, M, Verbeek, W, Trimble, V, Stevens, F, Kelleher, D, Barisani, D, Bardella, M, Mcmanus, R, van Heel, D, and Wijmenga, C

Subjects
Male, Linkage disequilibrium, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, TNFAIP3, Linkage Disequilibrium, Coeliac disease, 6Q23, REGION, INFLAMMATION, medicine, Humans, IMMUNE-RESPONSE, Genetic Predisposition to Disease, Risk factor, GENOME-WIDE ASSOCIATION, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Tumor Necrosis Factor alpha-Induced Protein 3, GENE-EXPRESSION, BIO/13 - BIOLOGIA APPLICATA, Intracellular Signaling Peptides and Proteins, NF-kappa B, Gastroenterology, Case-control study, Nuclear Proteins, celiac disease, NFkB, medicine.disease, RHEUMATOID-ARTHRITIS, DNA-Binding Proteins, Celiac Disease, A20, Case-Control Studies, Immunology, Female, Genes, rel, Signal Transduction
Abstract

Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p

Published
2009
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9. Cell Specific eQTL Analysis without Sorting Cells

Author

Julian C. Knight, Harm-Jan Westra, Joyce B. J. van Meurs, Ritsert C. Jansen, De Yun Wang, Christian Herder, Francesca Zolezzi, Uwe Völker, Michael Roden, Georg Homuth, Rinse K. Weersma, Jan H. Veldink, Konstantin Strauch, Benjamin P. Fairfax, Silva Kasela, Anis Larbi, Jingyuan Fu, Anand Kumar Andiappan, Veikko Salomaa, Markus Perola, Samuli Ripatti, Leonard H. van den Berg, Marjolein J. Peters, Yang Li, Olaf Rötzschke, Danny Arends, Tõnu Esko, Lili Milani, Bernett Lee, Harald Grallert, David Melzer, Fernando Rivadeneira, Albert Hofman, Eva Reinmaa, Andrew B. Singleton, Marijn C. Visschedijk, Astrid Petersmann, Lude Franke, Luigi Ferrucci, Andres Metspalu, Michael Poidinger, Holger Prokisch, Liina Tserel, Thomas Meitinger, Andrew R. Wood, Mathieu Platteel, Roberto Lorbeer, Katharina Schramm, André G. Uitterlinden, Rossella Melchiotti, Dena G. Hernandez, Hanieh Yaghootkar, Johannes Kettunen, Juha Karjalainen, Cisca Wijmenga, Claudia Schurmann, Seiko Makino, Pärt Peterson, Bioinformatics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Internal Medicine, Epidemiology, Dermatology, Institute for Molecular Medicine Finland, Clinicum, Samuli Olli Ripatti / Principal Investigator, Department of Public Health, Biostatistics Helsinki, Quantitative Genetics, and Complex Disease Genetics

Subjects
Cancer Research, BLOOD, Neutrophils, Nod2 Signaling Adaptor Protein, Genome-wide association study, VARIANTS, Meta-analysis, Gene expression, Monocytes, Blood, Genome-wide association studies, Principal component analysis, Gene mapping, 0302 clinical medicine, Crohn Disease, WIDE ASSOCIATION, HETEROGENEITY, Lymphocytes, DNA METHYLATION, Genetics (clinical), GENE-EXPRESSION, Genetics, Regulation of gene expression, Principal Component Analysis, 0303 health sciences, C100, C700, ACTIVE CROHNS-DISEASE, 3142 Public health care science, environmental and occupational health, 3. Good health, ddc, Phenotype, DNA methylation, Research Article, Cell type, lcsh:QH426-470, Quantitative Trait Loci, Locus (genetics), Single-nucleotide polymorphism, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Cell Line, 03 medical and health sciences, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Reproducibility of Results, lcsh:Genetics, Gene Expression Regulation, Expression quantitative trait loci, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus., Author Summary Many variants in the genome, including variants associated with disease, affect the expression of genes. These so-called expression quantitative trait loci (eQTL) can be used to gain insight in the downstream consequences of disease. While it has been shown that many disease-associated variants alter gene expression in a cell-type dependent manner, eQTL datasets for specific cell types may not always be available and their sample size is often limited. We present a method that is able to detect cell type specific effects within eQTL datasets that have been generated from whole tissues (which may be composed of many cell types), in our case whole blood. By combining numerous whole blood datasets through meta-analysis, we show that we are able to detect eQTL effects that are specific for neutrophils and lymphocytes (two blood cell types). Additionally, we show that the variants associated with some diseases may preferentially alter the gene expression in one of these cell types. We conclude that our method is an alternative method to detect cell type specific eQTL effects, that may complement generating cell type specific eQTL datasets and that may be applied on other cell types and tissues as well.

Published
2015

10. Serum lipid levels, body mass index, and their role in coronary artery calcification : a polygenic analysis

Author

Willem P.Th.M. Mali, Susanne Moebus, Mathieu Platteel, Per Hoffmann, Max A. Viergever, Jessica van Setten, Markus M. Nöthen, Harry J. de Koning, Vinicius Tragante, Joanna Smolonska, Paul I.W. de Bakker, Karl-Heinz Jöckel, Sonali Pechlivanis, Matthijs Oudkerk, Raimund Erbel, Pim A. de Jong, Ivana Išgum, Public Health, and Academic Medical Center

Subjects
Male, CALCIUM SCORE, Pathology, medicine.medical_specialty, Multifactorial Inheritance, PROVIDES INSIGHTS, Medizin, Genome-wide association study, BLOOD-PRESSURE, Body Mass Index, GENETIC ARCHITECTURE, Coronary artery disease, Belgium, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, medicine, Humans, COMPUTED-TOMOGRAPHY, Myocardial infarction, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Vascular Calcification, ASYMPTOMATIC INDIVIDUALS, Genetics (clinical), Netherlands, genome-wide association study, RISK PREDICTION, business.industry, nutritional and metabolic diseases, medicine.disease, Lipids, Arterial calcification, Blood pressure, myocardial infarction, MYOCARDIAL-INFARCTION, CARDIOVASCULAR-DISEASE, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Body mass index, Lung cancer screening, coronary artery disease, Calcification
Abstract

Background— Coronary artery calcification (CAC) is widely regarded as a cumulative lifetime measure of atherosclerosis, but it remains unclear what is the relationship between calcification and traditional risk factors for coronary artery disease (CAD) and myocardial infarction (MI). This study characterizes the genetic architecture of CAC by evaluating the overall impact of common alleles associated with CAD/MI and its traditional risk factors. Methods and Results— On the basis of summary-association results from the CARDIoGRAMplusC4D study of CAD/MI, we calculated polygenic risk scores in 2599 participants of the Dutch and Belgian Lung Cancer Screening (NELSON) trial, in whom quantitative CAC levels (Agatston scores) were determined from chest computerized tomographic imaging data. The most significant polygenic model explained ≈14% of the observed CAC variance ( P =1.6×10 –11 ), which points to a residual effect because of many as yet unknown loci that overlap between CAD/MI and CAC. In addition, we constructed risk scores based on published single-nucleotide polymorphism associations for traditional cardiovascular risk factors and tested these scores for association with CAC. We found nominally significant associations for genetic risk scores of low-density lipoprotein-cholesterol, total cholesterol, and body mass index, which were successfully replicated in 2182 individuals of the Heinz Nixdorf Recall Study. Conclusions— Pervasive polygenic sharing between CAC and CAD/MI suggests that a substantial fraction of the heritable risk for CAD/MI is mediated through arterial calcification. We also provide evidence that genetic variants associated with serum lipid levels and body mass index influence CAC levels.

Published
2015

11. Cell specific eQTL analysis without sorting cells

Author

Cisca Wijmenga, Albert Hofman, Andrew B. Singleton, Michael Roden, Thomas Meitinger, Mathieu Platteel, Katharina Schramm, Claudia Schurmann, Roberto Lorbeer, Christian Herder, Seiko Makino, Julian C. Knight, Harm-Jan Westra, Lude Franke, Anis Larbi, Veikko Salomaa, Marijn C. Visschedijk, Dena G. Hernandez, Konstantin Strauch, Holger Prokisch, Lili Milani, Fernando Rivadeneira, Francesca Zolezzi, Joyce B. J. van Meurs, Marjolein J. Peters, Samuli Ripatti, Leonard H. van den Berg, Jan H. Veldink, Markus Perola, André G. Uitterlinden, Rinse K. Weersma, Danny Arends, Pärt Peterson, Timouthy M. Frayling, Bernett Lee, David Melzer, Olaf Rötzschke, Anand Kumar Andiappan, Michael Poidinger, Yang Li, Andres Metspalu, Andrew R. Wood, Juha Karjalainen, Tõnu Esko, Harald Grallert, Uwe Völker, Luigi Ferrucci, Eva Reinmaa, Astrid Petersmann, De Yun Wang, Benjamin P. Fairfax, Jingyuan Fu, Georg Homuth, Liina Tserel, Rossella Melchiotti, Hanieh Yaghootkar, Ritsert C. Jansen, Silva Kasela, and Johannes Kettunen

Subjects
Cell specific, 0303 health sciences, Cell type, Sorting, Single-nucleotide polymorphism, Computational biology, Biology, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Expression quantitative trait loci, 030212 general & internal medicine, Whole Organism, 030304 developmental biology, Whole blood
Abstract

Expression quantitative trait locus (eQTL) mapping on tissue, organ or whole organism data can detect associations that are generic across cell types. We describe a new method to focus upon specific cell types without first needing to sort cells. We applied the method to whole blood data from 5,683 samples and demonstrate that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils.

Published
2014
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12. Whole-genome sequence variation, population structure and demographic history of the Dutch population

Author

Dana Vuzman, H. Eka D. Suchiman, Qibin Li, Alexandros Kanterakis, Vyacheslav Koval, Ning Li, Heorhiy Byelas, Steven J. Pitts, Manfred Kayser, Alexander Schönhuth, Elisabeth M. van Leeuwen, P. Eline Slagboom, Jessica van Setten, Lennart C. Karssen, Aaron Isaacs, Patrick Deelen, Cisca Wijmenga, Sara L. Pulit, Jan H. Veldink, David R. Cox, Purnima Sundar, Androniki Menelaou, Mathijs Kattenberg, Gonneke Willemsen, Shamil R. Sunyaev, Eric-Wubbo Lameijer, André G. Uitterlinden, Mark Stoneking, Marian Beekman, Najaf Amin, Johan T. den Dunnen, Pier Francesco Palamara, Martijn Vermaat, Barbera D. C. van Schaik, Abdel Abdellaoui, Sujie Cao, Hailiang Mei, Robert E. Handsaker, Kai Ye, Hongzhi Cao, Paul I.W. de Bakker, Mannis van Oven, Jun Wang, Paz Polak, Fernando Rivadeneira, Gert-Jan B. van Ommen, Anton J. M. de Craen, Steven A. McCarroll, Ben A. Oostra, Victor Guryev, Jayne Y. Hehir-Kwa, K. Joeri van der Velde, Peter de Knijff, Yuanping Du, Carolina Medina-Gomez, David van Enckevort, Shobha Potluri, Isaac J. Nijman, Martijn Dijkstra, Mathieu Platteel, Cornelia M. van Duijn, Leonard H. van den Berg, Jeroen F. J. Laros, Wigard P. Kloosterman, Pieter B. Neerincx, Yingrui Li, Laurent C. Francioli, Itsik Pe'er, Ruoyan Chen, Mingkun Li, Clara C. Elbers, Jasper A. Bovenberg, Karol Estrada, Morris A. Swertz, Jan Bot, Fereydoun Hormozdiari, Freerk van Dijk, Dorret I. Boomsma, Ivo Renkens, Mashaal Sohail, Tobias Marschall, Matthijs Moed, Albert Hofman, Jouke-Jan Hottenga, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Dermatology, Epidemiology, Genetic Identification, Medical Informatics, Internal Medicine, Clinical Genetics, Molecular Genetics, Adult Psychiatry, Epidemiology and Data Science, CCA -Cancer Center Amsterdam, ANS - Amsterdam Neuroscience, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, AII - Amsterdam institute for Infection and Immunity, and ACS - Amsterdam Cardiovascular Sciences

Subjects
Netherlands Twin Register (NTR), HAPLOTYPE MAP, Demographic history, IMPACT, Population, Biology, VARIANTS, Genome, Polymorphism, Single Nucleotide, White People, Structural variation, Gene Frequency, RARE, Genetic variation, Genetics, Humans, SDG 14 - Life Below Water, EXOMES, education, COMMON, Exome sequencing, Alleles, Netherlands, Whole genome sequencing, education.field_of_study, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genome, Human, GENETIC-VARIATION, Sequence Analysis, DNA, HUMAN-DISEASE, EVOLUTION, Mutagenesis, Insertional, Genetics, Population, Haplotypes, Evolutionary biology, DE-NOVO MUTATIONS, Imputation (genetics), Gene Deletion, Genome-Wide Association Study
Abstract

Contains fulltext : 137213.pdf (Publisher’s version ) (Closed access) Whole-genome sequencing enables complete characterization of genetic variation, but geographic clustering of rare alleles demands many diverse populations be studied. Here we describe the Genome of the Netherlands (GoNL) Project, in which we sequenced the whole genomes of 250 Dutch parent-offspring families and constructed a haplotype map of 20.4 million single-nucleotide variants and 1.2 million insertions and deletions. The intermediate coverage ( approximately 13x) and trio design enabled extensive characterization of structural variation, including midsize events (30-500 bp) previously poorly catalogued and de novo mutations. We demonstrate that the quality of the haplotypes boosts imputation accuracy in independent samples, especially for lower frequency alleles. Population genetic analyses demonstrate fine-scale structure across the country and support multiple ancient migrations, consistent with historical changes in sea level and flooding. The GoNL Project illustrates how single-population whole-genome sequencing can provide detailed characterization of genetic variation and may guide the design of future population studies.

Published
2014
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13. Common and different genetic background for rheumatoid arthritis and coeliac disease

Author

Mathieu Platteel, Chris J. J. Mulder, Harry J.M. Groen, Pilar Barrera, David A. van Heel, Wieke H. M. Verbeek, Alexandra Zhernakova, Elisabeth Brouwer, M. Luisa Mearin, Cisca Wijmenga, Piet L. C. M. van Riel, Greetje J. Tack, Joanna Smolonska, Sandra Heskamp, Roderick H. J. Houwen, Timothy R D J Radstake, Victorien M. Wolters, Willem P.Th.M. Mali, Pieter Zanen, Jan-Willem J. Lammers, Miek A. van Leeuwen, Gosia Trynka, Dirkje S. Postma, Marike Boezen, Barbara Franke, Marieke J H Coenen, Cleo C. van Diemen, Gastroenterology and hepatology, Other Research, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Life Course Epidemiology (LCE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Male, Genetics and epigenetic pathways of disease [NCMLS 6], Arthritis, Genome-wide association study, Coeliac disease, Arthritis, Rheumatoid, Cohort Studies, 0302 clinical medicine, Gene Frequency, Perception and Action [DCN 1], RISK VARIANTS, SYSTEMIC-LUPUS-ERYTHEMATOSUS, LIPOMA-PREFERRED PARTNER, Genetics (clinical), Netherlands, 0303 health sciences, education.field_of_study, General Medicine, FOCAL ADHESION, 3. Good health, ULCERATIVE-COLITIS, 030220 oncology & carcinogenesis, Female, Functional Neurogenomics [DCN 2], Infection and autoimmunity [NCMLS 1], Genotype, SUSCEPTIBILITY LOCI, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, AUTOIMMUNE-DISEASES, REGION, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular epidemiology [NCEBP 1], PTPN22, 03 medical and health sciences, Meta-Analysis as Topic, Genetics, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Molecular Biology, 030304 developmental biology, Genetic association, Autoimmune disease, RECEPTOR, Interleukins, Protein Tyrosine Phosphatase, Non-Receptor Type 22, medicine.disease, Celiac Disease, Evaluation of complex medical interventions [NCEBP 2], Immunology, Interleukin-2, Genome-Wide Association Study
Abstract

Contains fulltext : 81471.pdf (Publisher’s version ) (Closed access) Recent genome-wide association studies (GWAS) have revealed genetic risk factors in autoimmune and inflammatory disorders. Several of the associated genes and underlying pathways are shared by various autoimmune diseases. Rheumatoid arthritis (RA) and coeliac disease (CD) are two autoimmune disorders which have commonalities in their pathogenesis. We aimed to replicate known RA loci in a Dutch RA population, and to investigate whether the effect of known RA and CD risk factors generalize across the two diseases. We selected all loci associated to either RA or CD in a GWAS and confirmed in an independent cohort, with a combined P-value cut-off P < 5 x 10(-6). We genotyped 11 RA and 11 CD loci in 1368 RA patients, 795 CD patients and 1683 Dutch controls. We combined our results in a meta-analysis with UK GWAS on RA (1860 cases; 2938 controls) and CD (767 cases; 1422 controls). In the Dutch RA cohort, the PTPN22 and IL2/IL21 variants showed convincing association (P = 3.4 x 10(-12) and P = 2.8 x 10(-4), respectively). Association of RA with the known CD risk variant in the SH2B3 was also observed, predominantly in the subgroup of rheumatoid factor-positive RA patients (P = 0.0055). In a meta-analysis of Dutch and UK data sets, shared association with six loci (TNFAIP3, IL2/IL21, SH2B3, LPP, MMEL1/TNFRSF14 and PFKFB3/PRKCQ) was observed in both RA and CD cohorts. We confirmed two known loci and identified four novel ones for shared CD-RA genetic risk. Most of the shared loci further emphasize a role for adaptive and innate immunity in these diseases.

Published
2009
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14. HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma

Author

Alice Gallagher, Mathieu Platteel, Arjan Diepstra, Sibrand Poppema, Lydia Visser, Marijke Niens, Gerard J. te Meerman, Bouke G. Hepkema, Ruth F. Jarrett, Ilja M. Nolte, Niels Kouprie, Anke van den Berg, Craig Delury, Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), and Translational Immunology Groningen (TRIGR)

Subjects
Adult, Male, Epstein-Barr Virus Infections, Adolescent, EPITOPES, Immunology, PROTEIN, Single-nucleotide polymorphism, Human leukocyte antigen, PHENOTYPE, Major histocompatibility complex, medicine.disease_cause, SEQUENCE, Biochemistry, Polymorphism, Single Nucleotide, DISEASE, Virus, Antigen, Risk Factors, hemic and lymphatic diseases, HLA-A2 Antigen, medicine, Humans, Genetic Predisposition to Disease, EPSTEIN-BARR-VIRUS, REED-STERNBERG CELLS, HLA-A1 Antigen, Aged, Aged, 80 and over, biology, HLA-A Antigens, Cell Biology, Hematology, INFECTED CELLS, Middle Aged, HLA-CLASS-I, medicine.disease, Epstein–Barr virus, Hodgkin Disease, MAJOR HISTOCOMPATIBILITY COMPLEX, HLA-A, Reed–Sternberg cell, Haplotypes, biology.protein, Female
Abstract

Previous studies showed that the HLA class I region is associated with Epstein-Barr virus (EBV)–positive Hodgkin lymphoma (HL) and that HLA-A is the most likely candidate gene in this region. This suggests that antigenic presentation of EBV-derived peptides in the context of HLA-A is involved in the pathogenesis of EBV+ HL by precluding efficient immune responses. We genotyped exons 2 and 3, encoding the peptide-binding groove of HLA-A, for 32 single nucleotide polymorphisms in 70 patients with EBV+ HL, 31 patients with EBV− HL, and 59 control participants. HLA-A*01 was significantly overrepresented and HLA-A*02 was significantly underrepresented in patients with EBV+ HL versus controls and patients with EBV− HL. In addition, HLA-A*02 status was determined by immunohistochemistry or HLA-A*02–specific polymerase chain reaction (PCR) on 152 patients with EBV+ HL and 322 patients with EBV− HL. The percentage of HLA-A*02+ patients in the EBV+ HL group (35.5%) was significantly lower than in 6107 general control participants (53.0%) and the EBV− HL group (50.9%). Our results indicate that individuals carrying the HLA-A*02 allele have a reduced risk of developing EBV+ HL, while individuals carrying the HLA-A*01 allele have an increased risk. It is known that HLA-A*02 can present EBV-derived peptides and can evoke an effective immune response, which may explain the protective phenotype.

Published
2007

15. Erratum: Corrigendum: Multiple common variants for celiac disease influencing immune gene expression

Author

Patrick Dubois, Mathieu Platteel, Kalle Kurppa, Chris J. J. Mulder, Miguel Fernández-Arquero, Alexandra Zhernakova, Jihane Romanos, Roel A. Ophoff, Szilvia Fiatal, Maria Cristina Mazzilli, Graham A. Heap, Jan H. Veldink, David A. van Heel, Veikko Salomaa, Bárbara Dema, Róza Ádány, Maria Pia Sperandeo, Cisca Wijmenga, Leena Peltonen, Bożena Cukrowska, Maria Teresa Bardella, Padraic MacMathuna, Gosia Trynka, Concepción Núñez, Joseph A. Murray, Susan L. Neuhausen, Katherine I. Morley, Joachim J. Schweizer, Roderick H. J. Houwen, Karen A. Hunt, Elvira Grandone, Elvira Oosterom, M. Luisa Mearin, Barbara Mora, Donatella Barisani, Victorien M. Wolters, Katri Kaukinen, Charles A. Mein, Nicholas A. Bockett, Dermot Kelleher, Ilma Rita Korponay-Szabó, Markku Maeki, Rhian Gwilliam, Graham Turner, Jeffrey C. Barrett, Lude Franke, Alessandra Curtotti, Sarah E. Hunt, Elena Urcelay, Emilio G. de la Concha, Rinse K. Weersma, Leonard H. van den Berg, Peter M. Green, Harry J.M. Groen, Anna Rybak, Luigi Greco, Ross McManus, Muddassar M. Mirza, Vanisha Mistry, Greetje J. Tack, Päivi Saavalainen, O. T. McCann, Isabel Polanco, Rudolf S N Fehrmann, Wieke H. M. Verbeek, Arpo Aromaa, and Panos Deloukas

Subjects
Genetics, Disease, Biology, Bioinformatics, Immune gene
Abstract

Nat. Genet.; doi:10.1038/ng.543; corrected online 12 March 2010 In the version of this article initially published online, the P value ranges in the second paragraph of the Results section under (iii) and (iv) were noted incorrectly. These errors have been corrected for the print, PDF and HTML versions of this article.

Published
2010
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