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

doi:10.1038/gene.2011.3

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

Biochemistry & Molecular Biology

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30 Scopus citations

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 language	English (US)
Pages (from-to)	335-340
Number of pages	6
Journal	Genes and Immunity
Volume	12
Issue number	5
DOIs	https://doi.org/10.1038/gene.2011.3
State	Published - Jul 2011

All Science Journal Classification (ASJC) codes

Immunology
Genetics
Genetics(clinical)

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10.1038/gene.2011.3

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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. (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

@article{12160667a07e4fbc91ce466f689eac00,

title = "A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility",

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.",

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

note = "Funding Information: 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.",

year = "2011",

month = jul,

doi = "10.1038/gene.2011.3",

language = "English (US)",

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pages = "335--340",

journal = "Genes and Immunity",

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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

TY - JOUR

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.

N1 - Funding Information: 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.

PY - 2011/7

Y1 - 2011/7

N2 - 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.

AB - 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.

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

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