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A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility

Genes & Immunity volume 12, pages 335–340 (2011)Cite this article

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Abstract

Gene–gene interactions are proposed as an important component of the genetic architecture of complex diseases, and are just beginning to be evaluated in the context of genome-wide association studies (GWAS). In addition to detecting epistasis, a benefit to interaction analysis is that it also increases power to detect weak main effects. We conducted a knowledge-driven interaction analysis of a GWAS of 931 multiple sclerosis (MS) trios to discover gene–gene interactions within established biological contexts. We identify heterogeneous signals, including a gene–gene interaction between CHRM3 (muscarinic cholinergic receptor 3) and MYLK (myosin light-chain kinase) (joint P=0.0002), an interaction between two phospholipase C-β isoforms, PLCβ1 and PLCβ4 (joint P=0.0098), and a modest interaction between ACTN1 (actinin alpha 1) and MYH9 (myosin heavy chain 9) (joint P=0.0326), all localized to calcium-signaled cytoskeletal regulation. Furthermore, we discover a main effect (joint P=5.2E−5) previously unidentified by single-locus analysis within another related gene, SCIN (scinderin), a calcium-binding cytoskeleton regulatory protein. This work illustrates that knowledge-driven interaction analysis of GWAS data is a feasible approach to identify new genetic effects. The results of this study are among the first gene–gene interactions and non-immune susceptibility loci for MS. Further, the implicated genes cluster within inter-related biological mechanisms that suggest a neurodegenerative component to MS.

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Acknowledgements

This research was funded by the NIH grants 1R01 LM010040-01 and 5R01 NS049477-05. This study makes use of data generated by the WTCCC.

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

    W S Bush, S M Dudek, J L Haines & M D Ritchie

  2. Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA

    J L McCauley

  3. Division of Molecular Immunology, Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA

    P L DeJager & D A Hafler

  4. GlaxoSmithKline, Research & Development, Middlesex, UK

    R A Gibson & P M Matthews

  5. Department of Neurology, University Hospital Basel, Basel, Switzerland

    L Kappos & Y Naegelin

  6. Department of Neurology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands

    C H Polman

  7. Department of Neurology, School of Medicine, University of California, San Francisco, CA, USA

    S L Hauser & J Oksenberg

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  1. W S Bush
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Correspondence to M D Ritchie.

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Bush, W., McCauley, J., DeJager, P. et al. A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility. Genes Immun 12, 335–340 (2011). https://doi.org/10.1038/gene.2011.3

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