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

W. S. Bush, J. L. McCauley, P. L. Dejager, S. M. Dudek, D. A. Hafler, R. A. Gibson, P. M. Matthews, L. Kappos, Y. Naegelin, C. H. Polman, S. L. Hauser, J. Oksenberg, J. L. Haines, M. D. Ritchie

Research output: Contribution to journalArticle

25 Citations (Scopus)

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=5.2E5) 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.

Original languageEnglish (US)
Pages (from-to)335-340
Number of pages6
JournalGenes and Immunity
Volume12
Issue number5
DOIs
StatePublished - Jul 1 2011

Fingerprint

Multiple Sclerosis
Genes
Genome-Wide Association Study
Joints
Calcium
Ventricular Myosins
Myosin-Light-Chain Kinase
Actinin
Myosin Heavy Chains
Type C Phospholipases
Cholinergic Receptors
Muscarinic Receptors
Multigene Family
Cytoskeleton
Protein Isoforms

All Science Journal Classification (ASJC) codes

  • Immunology
  • Genetics
  • Genetics(clinical)

Cite this

Bush, W. S., McCauley, J. L., Dejager, P. L., Dudek, S. M., Hafler, D. A., Gibson, R. A., ... Ritchie, M. D. (2011). A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility. Genes and Immunity, 12(5), 335-340. https://doi.org/10.1038/gene.2011.3
Bush, W. S. ; McCauley, J. L. ; Dejager, P. L. ; Dudek, S. M. ; Hafler, D. A. ; Gibson, R. A. ; Matthews, P. M. ; Kappos, L. ; Naegelin, Y. ; Polman, C. H. ; Hauser, S. L. ; Oksenberg, J. ; Haines, J. L. ; Ritchie, M. D. / A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility. In: Genes and Immunity. 2011 ; Vol. 12, No. 5. pp. 335-340.
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Bush, WS, McCauley, JL, Dejager, PL, Dudek, SM, Hafler, DA, Gibson, RA, Matthews, PM, Kappos, L, Naegelin, Y, Polman, CH, Hauser, SL, Oksenberg, J, Haines, JL & Ritchie, MD 2011, 'A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility', Genes and Immunity, vol. 12, no. 5, pp. 335-340. https://doi.org/10.1038/gene.2011.3

A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility. / Bush, W. S.; McCauley, J. L.; Dejager, P. L.; Dudek, S. M.; Hafler, D. A.; Gibson, R. A.; Matthews, P. M.; Kappos, L.; Naegelin, Y.; Polman, C. H.; Hauser, S. L.; Oksenberg, J.; Haines, J. L.; Ritchie, M. D.

In: Genes and Immunity, Vol. 12, No. 5, 01.07.2011, p. 335-340.

Research output: Contribution to journalArticle

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T1 - A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility

AU - Bush, W. S.

AU - McCauley, J. L.

AU - Dejager, P. L.

AU - Dudek, S. M.

AU - Hafler, D. A.

AU - Gibson, R. A.

AU - Matthews, P. M.

AU - Kappos, L.

AU - Naegelin, Y.

AU - Polman, C. H.

AU - Hauser, S. L.

AU - Oksenberg, J.

AU - Haines, J. L.

AU - Ritchie, M. D.

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