A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Rosella Mechelli, Renato Umeton, Claudia Policano, Viviana Annibali, Giulia Coarelli, Vito A.G. Ricigliano, Danila Vittori, Arianna Fornasiero, Maria Chiara Buscarinu, Silvia Romano, Marco Salvetti, Giovanni Ristori, Stephen Sawcer, Garrett Hellenthal, Matti Pirinen, Chris C.A. Spencer, Nikolaos A. Patsopoulos, Loukas Moutsianas, Alexander Dilthey, Zhan SuColin Freeman, Sarah E. Hunt, Sarah Edkins, Emma Gray, David R. Booth, Simon C. Potter, An Goris, Gavin Band, Annette Bang Oturai, Amy Strange, Janna Saarela, Céline Bellenguez, Bertrand Fontaine, Matthew Gillman, Bernhard Hemmer, Rhian Gwilliam, Frauke Zipp, Alagurevathi Jayakumar, Roland Martin, Stephen Leslie, Stanley Hawkins, Eleni Giannoulatou, Sandra D'alfonso, Hannah Blackburn, Filippo Martinelli Boneschi, Jennifer Liddle, Hanne F. Harbo, Marc L. Perez, Anne Spurkland, Matthew J. Waller, Marcin P. Mycko, Michelle Ricketts, Manuel Comabella, Naomi Hammond, Ingrid Kockum, Owen T. McCann, Maria Ban, Pamela Whittaker, Anu Kemppinen, Paul Weston, Clive Hawkins, Sara Widaa, John Zajicek, Serge Dronov, Neil Robertson, Suzannah J. Bumpstead, Lisa F. Barcellos, Rathi Ravindrarajah, Roby Abraham, Lars Alfredsson, Kristin Ardlie, Cristin Aubin, Amie Baker, Katharine Baker, Sergio E. Baranzini, Laura Bergamaschi, Roberto Bergamaschi, Allan Bernstein, Achim Berthele, Mike Boggild, Jonathan P. Bradfield, David Brassat, Simon A. Broadley, Dorothea Buck, Helmut Butzkueven, Ruggero Capra, William M. Carroll, Paola Cavalla, Elisabeth G. Celius, Sabine Cepok, Rosetta Chiavacci, Françoise Clerget-Darpoux, Katleen Clysters, Giancarlo Comi, Mark Cossburn, Isabelle Cournu-Rebeix, Mathew B. Cox, Wendy Cozen, Bruce A.C. Cree, Anne H. Cross, Daniele Cusi, Mark J. Daly, Emma Davis, Paul I.W. de Bakker, Marc Debouverie, Marie Beatrice D'hooghe, Katherine Dixon, Rita Dobosi, Bénédicte Dubois, David Ellinghaus, Irina Elovaara, Federica Esposito, Claire Fontenille, Simon Foote, Andre Franke, Daniela Galimberti, Angelo Ghezzi, Joseph Glessner, Refujia Gomez, Olivier Gout, Colin Graham, Struan F.A. Grant, Franca Rosa Guerini, Hakon Hakonarson, Per Hall, Anders Hamsten, Hans Peter Hartung, Rob N. Heard, Simon Heath, Jeremy Hobart, Muna Hoshi, Carmen Infante-Duarte, Gillian Ingram, Wendy Ingram, Talat Islam, Maja Jagodic, Michael Kabesch, Allan G. Kermode, Trevor J. Kilpatrick, Cecilia Kim, Norman Klopp, Keijo Koivisto, Malin Larsson, Mark Lathrop, Jeannette S. Lechner-Scott, Maurizio A. Leone, Virpi Leppä, Ulrika Liljedahl, Izaura Lima Bomfim, Robin R. Lincoln, Jenny Link, Jianjun Liu, Åslaug R. Lorentzen, Sara Lupoli, Fabio Macciardi, Thomas Mack, Mark Marriott, Vittorio Martinelli, Deborah Mason, Jacob L. McCauley, Frank Mentch, Inger Lise Mero, Tania Mihalova, Xavier Montalban, John Mottershead, Kjell Morten Myhr, Paola Naldi, William Ollier, Alison Page, Aarno Palotie, Jean Pelletier, Laura Piccio, Trevor Pickersgill, Fredrik Piehl, Susan Pobywajlo, Hong L. Quach, Patricia P. Ramsay, Mauri Reunanen, Richard Reynolds, John D. Rioux, Mariaemma Rodegher, Sabine Roesner, Justin P. Rubio, Ina Maria Rückert, Erika Salvi, Adam Santaniello, Catherine A. Schaefer, Stefan Schreiber, Christian Schulze, Rodney J. Scott, Finn Sellebjerg, Krzysztof W. Selmaj, David Sexton, Ling Shen, Brigid Simms-Acuna, Sheila Skidmore, Patrick M.A. Sleiman, Cathrine Smestad, Per Soelberg Sørensen, Helle Bach Søndergaard, Jim Stankovich, Richard C. Strange, Anna Maija Sulonen, Emilie Sundqvist, Ann Christine Syvänen, Francesca Taddeo, Bruce Taylor, Jenefer M. Blackwell, Pentti Tienari, Elvira Bramon, Ayman Tourbah, Matthew A. Brown, Ewa Tronczynska, Juan P. Casas, Niall Tubridy, Aiden Corvin, Jane Vickery, Janusz Jankowski, Pablo Villoslada, Hugh S. Markus, Kai Wang, Christopher G. Mathew, James Wason, Colin N.A. Palmer, H. Erich Wichmann, Robert Plomin, Ernest Willoughby, Anna Rautanen, Juliane Winkelmann, Michael Wittig, Richard C. Trembath, Jacqueline Yaouanq, Ananth C. Viswanathan, Haitao Zhang, Nicholas W. Wood, Rebecca Zuvich, Panos Deloukas, Cordelia Langford, Audrey Duncanson, Jorge R. Oksenberg, Margaret A. Pericak-Vance, Jonathan L. Haines, Tomas Olsson, Jan Hillert, Adrian J. Ivinson, Philip L. De Jager, Leena Peltonen, Graeme J. Stewart, David A. Hafler, Stephen L. Hauser, Gil McVean, Peter Donnelly, Alastair Compston

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Abstract

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms.

Original languageEnglish
Article numbere63300
JournalPloS one
Volume8
Issue number5
DOIs
StatePublished - May 16 2013

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    Mechelli, R., Umeton, R., Policano, C., Annibali, V., Coarelli, G., Ricigliano, V. A. G., Vittori, D., Fornasiero, A., Buscarinu, M. C., Romano, S., Salvetti, M., Ristori, G., Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C. C. A., Patsopoulos, N. A., Moutsianas, L., Dilthey, A., ... Compston, A. (2013). A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis. PloS one, 8(5), [e63300]. https://doi.org/10.1371/journal.pone.0063300