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A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility.
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 1195716
Author(s) 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; International Multiple Sclerosis Genetics Consortium
Author(s) at UniBasel Kappos, Ludwig
Year 2011
Title A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility.
Journal Genes and immunity
Volume 12
Number 5
Pages / Article-Number 335-40
Keywords multiple sclerosis, knowledge-driven interaction, neurodegenerative mechanism
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-? isoforms, PLC?1 and PLC?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.
Publisher Nature Publ. Group
ISSN/ISBN 1466-4879
edoc-URL http://edoc.unibas.ch/dok/A6005897
Full Text on edoc No
Digital Object Identifier DOI 10.1038/gene.2011.3
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/21346779
ISI-Number WOS:000292968500002
Document type (ISI) Journal Article
 
   

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