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A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility

Genes & Immunity volume 15, pages 126–132 (2014)Cite this article

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Abstract

Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood–brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL, ICAM1 and ICAM3 genes, could be of interest to develop novel therapeutic targets.

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Acknowledgements

This study was supported by the Institut National de la Santé et de la Recherche Médicale, the Fondation pour la Recherche sur la Sclérose En Plaques (ARSEP), the Association Française contre les Myopathies, GIS-IBISA and ICM Carnot Institute. The research leading to these results has received funding from the program ‘Investissements d’avenir’ ANR-10-IAIHU-06. We thank ICM, CIC Pitié-Salpêtrière, Généthon, BRC-REFGENSEP’s and IMSGC’s members for their help and support as well as Jorge Oksenberg and Pierre-Antoine Gourraud. VD received a travel grant from the Fondation ARSEP and ICM Carnot Institute. Philip L De Jager is a Harry Weaver Neuroscience Scholar of the National MS Society. SEB is a Harry Weaver Neuroscience fellow from the US National MS Society. This investigation was supported (in part) by a Postdoctoral Fellowship from the National Multiple Sclerosis Society to Nikolaos A Patsopoulos (FG 1938-A-1).

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Author notes

  1. I Cournu-Rebeix and B Fontaine: These authors contributed equally to this work.

Authors and Affiliations

  1. UPMC-INSERM-UMR_S 1127-CNRS UMR7225, Paris, France

    V Damotte, L Guillot-Noel, M El Behi, I Cournu-Rebeix & B Fontaine

  2. Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham & Women's Hospital, Boston, MA, USA

    N A Patsopoulos & P L De Jager

  3. Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA

    N A Patsopoulos

  4. Harvard Medical School, Boston, MA, USA

    N A Patsopoulos & P L De Jager

  5. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA

    N A Patsopoulos & P L De Jager

  6. Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, San Francisco, CA, USA

    L Madireddy & S E Baranzini

  7. Institut du Cerveau et de la Moelle épinière-ICM, Paris, France

    M El Behi

  8. Département des Maladies du Systéme Nerveux, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France

    I Cournu-Rebeix & B Fontaine

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International Multiple Sclerosis Genetics Consortium

  • Maria Ban
  • , Sergio Baranzini
  • , Lisa Barcellos
  • , Gary Beecham
  • , Ashley Beecham
  • , Luisa Bernardinelli
  • , David Booth
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  • , Isabelle Cournu-Rebeix
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  • , Vincent Damotte
  • , Mary Davis
  • , Paul de Bakker
  • , Philip L De Jager
  • , Benedicte Dubois
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  • , Bertrand Fontaine
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  • , Annette Oturai
  • , Aarno Palotie
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  • , Margaret Pericak-Vance
  • , John Rioux
  • , Janna Saarela
  • , Stephen Sawcer
  • , Nathalie Schnetz-Boutaud
  • , Finn Sellebjerg
  • , Helle Soendergaard
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  • , Elvira Bramon
  • , Matthew A Brown
  • , Juan P Casas
  • , Aiden Corvin
  • , Janusz Jankowski
  • , Hugh S Markus
  • , Christopher G Mathew
  • , Colin N A Palmer
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  • , Anna Rautanen
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  • , Richard C Trembath
  • , Ananth C Viswanathan
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  • , Chris C A Spencer
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  • , Colin Freeman
  • , Garrett Hellenthal
  • , Eleni Giannoulatou
  • , Matti Pirinen
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Corresponding author

Correspondence to B Fontaine.

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The authors declare no conflict of interest.

Additional information

Maria Ban, Sergio Baranzini, Lisa Barcellos, Gary Beecham, Ashley Beecham, Luisa Bernardinelli, David Booth, Steffan Bos, Dorothea Buck, William Bush, Manuel Comabella, Alastair Compston, Chris Cotsapas, Isabelle Cournu-Rebeix, Bruce Cree, Sandra D'Alfonso, Mark Daly, Vincent Damotte, Mary Davis, Paul de Bakker, Philip L De Jager, Benedicte Dubois, Federica Esposito, Bertrand Fontaine, An Goris, Pierre-Antoine Gourraud, Todd Green, Elisabeth Gulowsen Celius, Athena Hadjixenofontos, David Hafler, Jonathan Haines, Hanne F Harbo, Stephen Hauser, Clive Hawkins, Bernhard Hemmer, Jan Hillert, Rogier Hintzen, Dana Horáková, Adrian J Ivinson, Anu Kemppinen, Jun-ichi Kira, Ingrid Kockum, Robin Lincoln, Roland Martin, Filippo Martinelli Boneschi, Jacob L McCauley, Inger-Lise Mero, Jorge Oksenberg, Tomas Olsson, Annette Oturai, Aarno Palotie, Nikolaos Patsopoulos, Margaret Pericak-Vance, John Rioux, Janna Saarela, Stephen Sawcer, Nathalie Schnetz-Boutaud, Finn Sellebjerg, Helle Soendergaard, Per Soelberg Sorensen, Anne Spurkland, Jim Stankovich, Graeme Stewart, Bruce Taylor, Anna Ticca, Sandra West and Frauke Zipp.

Management Committee: Peter Donnelly (Chair), Ines Barroso (Deputy Chair), Jenefer M. Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin NA Palmer, Robert Plomin, Anna Rautanen, Stephen Sawcer, Richard C Trembath, Ananth C Viswanathan and Nicholas W Wood. Data and Analysis Group: Chris CA Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic and Peter Donnelly. DNA, Genotyping, Data QC and Informatics Group: Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Rathi Ravindrarajah, Michelle Ricketts, Matthew J Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso and Panos Deloukas. Associate Members: Alexander Dilthey, Stephen Leslie, Loukas Moutsianas, Marc L Perez and Gil McVean. Publications Committee: Christopher G Mathew, Jenefer M Blackwell, Matthew A Brown, Aiden Corvin, Mark I McCarthy and Chris CA Spencer.

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Damotte, V., Guillot-Noel, L., Patsopoulos, N. et al. A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility. Genes Immun 15, 126–132 (2014). https://doi.org/10.1038/gene.2013.70

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