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

W. S. Bush, Jacob 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

24 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
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

Keywords

  • knowledge-driven interaction
  • Multiple sclerosis
  • neurodegenerative mechanism

ASJC Scopus subject areas

  • Genetics(clinical)
  • Immunology
  • Genetics

Cite this

A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility. / Bush, W. S.; McCauley, Jacob 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

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
Bush, W. S. ; McCauley, Jacob 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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