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

共 39 条

[21] Risk alleles for multiple sclerosis identified by a genomewide study [J].

Hafler, David A. ;

Compston, Alastair ;

Sawcer, Stephen ;

Lander, Eric S. ;

Daly, Mark J. ;

De Jager, Philip L. ;

de Bakker, Paul I. W. ;

Gabriel, Stacey B. ;

Mirel, Daniel B. ;

Ivinson, Adrian J. ;

Pericak-Vance, Margaret A. ;

Gregory, Simon G. ;

Rioux, John D. ;

McCauley, Jacob L. ;

Haines, Jonathan L. ;

Barcellos, Lisa F. ;

Cree, Bruce ;

Oksenberg, Jorge R. ;

Hauser, Stephen L. .

NEW ENGLAND JOURNAL OF MEDICINE, 2007, 357 (09) :851-862

[22] TISSUE-SPECIFIC AND CELL TYPE-SPECIFIC EXPRESSION OF MESSENGER-RNAS FOR 4 TYPES OF INOSITOL PHOSPHOLIPID-SPECIFIC PHOSPHOLIPASE-C [J].

HOMMA, Y ;

TAKENAWA, T ;

EMORI, Y ;

SORIMACHI, H ;

SUZUKI, K .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1989, 164 (01) :406-412

[23]

Jian XY, 1996, J NEUROBIOL, V31, P379, DOI 10.1002/(SICI)1097-4695(199611)31:3<379::AID-NEU10>3.0.CO

[24]

2-B

[25] Phospholipase C isozymes selectively couple to specific neurotransmitter receptors [J].

Kim, D ;

Jun, KS ;

Lee, SB ;

Kang, NG ;

Min, DS ;

Kim, YH ;

Ryu, SH ;

Suh, PG ;

Shin, HS .

NATURE, 1997, 389 (6648) :290-293

[26] Brain-specific splicing of α-actinin 1 mRNA [J].

Kremerskothen, J ;

Teber, I ;

Wendholt, D ;

Liedtke, T ;

Böckers, TM ;

Barnekow, A .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2002, 295 (03) :678-681

[27] Susceptibility to glaucoma: differential comparison of the astrocyte transcriptome from glaucomatous African American and Caucasian American donors [J].

Lukas, Thomas J. ;

Miao, Haixi ;

Chen, Lin ;

Riordan, Sean M. ;

Li, Wenjun ;

Crabb, Andrea M. ;

Wise, Alexandria ;

Du, Pan ;

Lin, Simon M. ;

Hernandez, M. Rosario .

GENOME BIOLOGY, 2008, 9 (07)

[28] Genome-wide strategies for detecting multiple loci that influence complex diseases [J].

Marchini, J ;

Donnelly, P ;

Cardon, LR .

NATURE GENETICS, 2005, 37 (04) :413-417

[29] Clinical and molecular genetic analysis of a family with macrothrombocytopenia and early onset sensorineural hearing loss [J].

Mhatre, Anand N. ;

Janssens, Sandra ;

Nardi, Michael A. ;

Li, Yan ;

Lalwani, Anil K. .

EUROPEAN JOURNAL OF MEDICAL GENETICS, 2009, 52 (04) :185-190

[30]

MILLS GB, 1985, J IMMUNOL, V134, P1640

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