Christina M Lill1, Felix Luessi2, Antonio Alcina3, Ekaterina A Sokolova4, Nerea Ugidos5, Belén de la Hera6, Léna Guillot-Noël7, Sunny Malhotra8, Eva Reinthaler9, Brit-Maren M Schjeide10, Julia Y Mescheriakova11, Andriy Mashychev12, Inken Wohlers12, Denis A Akkad13, Orhan Aktas14, Iraide Alloza15, Alfredo Antigüedad16, Rafa Arroyo17, Ianire Astobiza5, Paul Blaschke18, Alexei N Boyko19, Mathias Buttmann20, Andrew Chan21, Thomas Dörner22, Joerg T Epplen23, Olga O Favorova24, Maria Fedetz3, Oscar Fernández25, Angel García-Martínez6, Lisa-Ann Gerdes26, Christiane Graetz2, Hans-Peter Hartung14, Sabine Hoffjan13, Guillermo Izquierdo27, Denis S Korobko28, Antje Kroner29, Christian Kubisch30, Tania Kümpfel26, Laura Leyva25, Peter Lohse31, Nadezhda A Malkova32, Xavier Montalban8, Ekaterina V Popova19, Peter Rieckmann33, Alexei S Rozhdestvenskii34, Christiane Schmied9, Inna V Smagina35, Ekaterina Y Tsareva24, Alexander Winkelmann18, Uwe K Zettl18, Harald Binder36, Isabelle Cournu-Rebeix7, Rogier Hintzen11, Alexander Zimprich9, Manuel Comabella8, Bertrand Fontaine37, Elena Urcelay6, Koen Vandenbroeck15, Maxim Filipenko4, Fuencisla Matesanz3, Frauke Zipp2, Lars Bertram38. 1. Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany. 2. Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. 3. Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, Granada, Spain. 4. Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Siberian Division, Russian Academy of Sciences, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia. 5. Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), Leioa, Spain Achucarro Basque Center for Neuroscience, Zamudio, Spain. 6. Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. 7. Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM F-75013, Paris, France. 8. Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall d´Hebron (HUVH), Barcelona, Spain. 9. Department of Neurology, Medical University of Vienna, Vienna, Austria. 10. Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany. 11. Department of Neurology, MS Centre ErasMS, Erasmus Medical Centre, Rotterdam, The Netherlands. 12. Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany. 13. Department of Human Genetics, Ruhr University, Bochum, Germany. 14. Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. 15. Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), Leioa, Spain Achucarro Basque Center for Neuroscience, Zamudio, Spain IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. 16. Servicio de Neurología, Hospital Universitario de Basurto, Bilbao, Spain. 17. Multiple Sclerosis Unit, Neurology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. 18. Department of Neurology, University of Rostock, Rostock, Germany. 19. Department of Neurology and Neurosurgery, Pirogov Russian National Research Medical University (RNRMU), Moscow, Russia. 20. Department of Neurology, University of Würzburg, Würzburg, Germany. 21. Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany. 22. Department of Medicine, Rheumatology, and Clinical Immunology & DRFZ, Charité University Medicine, Berlin, Germany. 23. Department of Neurology, MS Centre ErasMS, Erasmus Medical Centre, Rotterdam, The Netherlands Faculty of Health, University Witten/Herdecke, Witten, Germany. 24. Department of Molecular Biology and Medical Biotechnology, Pirogov Russian National Research Medical University (RNRMU), Moscow, Russia. 25. Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain. 26. Institute of Clinical Neuroimmunology, Campus Grosshadern, Ludwig Maximilian University, Munich, Germany. 27. Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain. 28. Multiple Sclerosis Center, Novosibirsk Regional State Clinical Hospital, Novosibirsk, Russia. 29. Department of Neurology, University of Würzburg, Würzburg, Germany Medical College of Wisconsin, Milwaukee, Wisconsin, USA. 30. Institute of Human Genetics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. 31. Department of Clinical Chemistry, Ludwig Maximilian University, Munich, Germany CeGaT GmbH, Tuebingen, Germany. 32. Multiple Sclerosis Center, Novosibirsk Regional State Clinical Hospital, Novosibirsk, Russia Department of Clinical Neurology and Algology, Novosibirsk State Medical University, Novosibirsk, Russia. 33. Department of Neurology, University of Würzburg, Würzburg, Germany Department of Neurology, Sozialstiftung Bamberg Hospital, Bamberg, Germany. 34. Department of Neurology of Postgraduate Education, Omsk State Medical Academy, Omsk, Russia. 35. Territorial Clinical Hospital, Barnaul, Russia Department of Nervous Diseases, Altai State Medical University, Barnaul, Russia. 36. Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany. 37. Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM F-75013, Paris, France AP-HP, Départment of des Maladies du Système Nerveux, Pitié-Salpêtrère Hospital, Paris, France. 38. Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany Department of Medicine, School of Public Health, Imperial College London, London, UK.
Abstract
OBJECTIVE: A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. METHODS: The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. RESULTS: Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10(-12)), CD28 (rs6435203, p=1.35×10(-9)), LPP (rs4686953, p=3.35×10(-8)), ETS1 (rs3809006, p=7.74×10(-9)), DLEU1 (rs806349, p=8.14×10(-12)), LPIN3 (rs6072343, p=7.16×10(-12)) and IFNGR2 (rs9808753, p=4.40×10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. CONCLUSIONS: This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
OBJECTIVE: A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. METHODS: The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. RESULTS: Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10(-12)), CD28 (rs6435203, p=1.35×10(-9)), LPP (rs4686953, p=3.35×10(-8)), ETS1 (rs3809006, p=7.74×10(-9)), DLEU1 (rs806349, p=8.14×10(-12)), LPIN3 (rs6072343, p=7.16×10(-12)) and IFNGR2 (rs9808753, p=4.40×10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. CONCLUSIONS: This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Hamish W King; Kristen L Wells; Zohar Shipony; Arwa S Kathiria; Lisa E Wagar; Caleb Lareau; Nara Orban; Robson Capasso; Mark M Davis; Lars M Steinmetz; Louisa K James; William J Greenleaf Journal: Sci Immunol Date: 2021-10-08
Authors: Till F M Andlauer; Dorothea Buck; Gisela Antony; Antonios Bayas; Lukas Bechmann; Achim Berthele; Andrew Chan; Christiane Gasperi; Ralf Gold; Christiane Graetz; Jürgen Haas; Michael Hecker; Carmen Infante-Duarte; Matthias Knop; Tania Kümpfel; Volker Limmroth; Ralf A Linker; Verena Loleit; Felix Luessi; Sven G Meuth; Mark Mühlau; Sandra Nischwitz; Friedemann Paul; Michael Pütz; Tobias Ruck; Anke Salmen; Martin Stangel; Jan-Patrick Stellmann; Klarissa H Stürner; Björn Tackenberg; Florian Then Bergh; Hayrettin Tumani; Clemens Warnke; Frank Weber; Heinz Wiendl; Brigitte Wildemann; Uwe K Zettl; Ulf Ziemann; Frauke Zipp; Janine Arloth; Peter Weber; Milena Radivojkov-Blagojevic; Markus O Scheinhardt; Theresa Dankowski; Thomas Bettecken; Peter Lichtner; Darina Czamara; Tania Carrillo-Roa; Elisabeth B Binder; Klaus Berger; Lars Bertram; Andre Franke; Christian Gieger; Stefan Herms; Georg Homuth; Marcus Ising; Karl-Heinz Jöckel; Tim Kacprowski; Stefan Kloiber; Matthias Laudes; Wolfgang Lieb; Christina M Lill; Susanne Lucae; Thomas Meitinger; Susanne Moebus; Martina Müller-Nurasyid; Markus M Nöthen; Astrid Petersmann; Rajesh Rawal; Ulf Schminke; Konstantin Strauch; Henry Völzke; Melanie Waldenberger; Jürgen Wellmann; Eleonora Porcu; Antonella Mulas; Maristella Pitzalis; Carlo Sidore; Ilenia Zara; Francesco Cucca; Magdalena Zoledziewska; Andreas Ziegler; Bernhard Hemmer; Bertram Müller-Myhsok Journal: Sci Adv Date: 2016-06-17 Impact factor: 14.136