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Complex gene–gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes

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Abstract

The complex inheritance involved in multiple sclerosis (MS) risk has been extensively investigated, but our understanding of MS genetics remains rudimentary. In this study, we explore 51 single nucleotide polymorphisms (SNPs) in 36 candidate genes from the inflammatory pathway and test for gene–gene interactions using complementary case–control, discordant sibling pair, and trio family study designs. We used a sample of 421 carefully diagnosed MS cases and 96 unrelated, healthy controls; discordant sibling pairs from 146 multiplex families; and 275 trio families. We used multifactor dimensionality reduction to explore gene–gene interactions. Based on our analyses, we have identified several statistically significant models including both main effect models and two-locus, three-locus, and four-locus epistasis models that predict MS disease risk with between ∼61% and 85% accuracy. These results suggest that significant epistasis, or gene–gene interactions, may exist even in the absence of statistically significant individual main effects.

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Acknowledgments

We are grateful to the MS patients and their families for participating in this study. This work was funded by grants RG2901 from the National Multiple Sclerosis Society and by National Institutes of Health grants NS026799, GM31304, AG20135, GM62758, NS32830, and in part by HL65962, the Pharmacogenomics of Arrhythmia Therapy U01 site of the Pharmacogenetics Research Network.

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Authors and Affiliations

  1. Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, 519 Light Hall, Vanderbilt University Medical School, Nashville, TN, 37232-0700, USA

    Alison A. Motsinger, Jonathan L. Haines & Marylyn D. Ritchie

  2. Department of Neurology and Center for Human Genetics, School of Medicine, University of California at San Francisco, San Francisco, CA, 94143, USA

    David Brassat, Stacy J. Caillier, Stephen L. Hauser & Jorge R. Oksenberg

  3. Department of Human Genetics, Roche Molecular Systems, Alameda, CA, 94501, USA

    Henry A. Erlich, Karen Walker & Lori L. Steiner

  4. Division of Epidemiology, School of Public Health, UC Berkeley, Berkeley, CA, 94720, USA

    Lisa F. Barcellos

  5. Center for Human Genetics, Duke University Medical Center, Durham, NC, 27710, USA

    Margaret A. Pericak-Vance, Silke Schmidt & Simon Gregory

Authors
  1. Alison A. Motsinger
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  2. David Brassat
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  3. Stacy J. Caillier
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  4. Henry A. Erlich
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  6. Lori L. Steiner
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  7. Lisa F. Barcellos
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  8. Margaret A. Pericak-Vance
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  11. Stephen L. Hauser
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  12. Jonathan L. Haines
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  13. Jorge R. Oksenberg
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  14. Marylyn D. Ritchie
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Corresponding author

Correspondence to Marylyn D. Ritchie.

Additional information

Alison A. Motsinger and David Brassat contributed equally to this work.

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Motsinger, A.A., Brassat, D., Caillier, S.J. et al. Complex gene–gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes. Neurogenetics 8, 11–20 (2007). https://doi.org/10.1007/s10048-006-0058-9

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  • DOI: https://doi.org/10.1007/s10048-006-0058-9

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