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

被引：21

作者：

Bush, W. S. ^{[1
]}

McCauley, J. L. ^{[2
]}

DeJager, P. L. ^{[3
,4
]}

Dudek, S. M. ^{[1
]}

Hafler, D. A. ^{[3
,4
]}

Gibson, R. A. ^{[5
]}

Matthews, P. M. ^{[5
]}

Kappos, L. ^{[6
]}

Naegelin, Y. ^{[6
]}

Polman, C. H. ^{[7
]}

Hauser, S. L. ^{[8
]}

Oksenberg, J. ^{[8
]}

Haines, J. L. ^{[1
]}

Ritchie, M. D. ^{[1
]}

机构：

[1] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA

[2] Univ Miami, Miller Sch Med, Miami Inst Human Genom, Miami, FL 33136 USA

[3] Brigham & Womens Hosp, Div Mol Immunol, Ctr Neurol Dis, Dept Neurol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Boston, MA USA

[5] GlaxoSmithKline, Res & Dev, Middlesex, England

[6] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland

[7] Vrije Univ Med Ctr, Dept Neurol, Amsterdam, Netherlands

[8] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA USA

来源：

GENES AND IMMUNITY | 2011年 / 12卷 / 05期

关键词：

multiple sclerosis; knowledge-driven interaction; neurodegenerative mechanism; GENOME-WIDE ASSOCIATION; LIGHT-CHAIN KINASE; PATHWAY ANALYSIS; GENETIC ASSOCIATION; UP-REGULATION; REPLICATION; EXPRESSION; MESSENGER; DYNAMICS; BINDING;

D O I：

10.1038/gene.2011.3

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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-beta isoforms, PLC beta 1 and PLC beta 4 (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. Genes and Immunity (2011) 12, 335-340; doi:10.1038/gene.2011.3; published online 24 February 2011

引用

页码：335 / 340

页数：6

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