Imperial College London

Professor Paul M. Matthews

Faculty of MedicineDepartment of Medicine

Edmond and Lily Safra Chair and Head of Brain Sciences



+44 (0)20 7594 2855p.matthews




Ms Siobhan Dillon +44 (0)20 7594 2855




E502Burlington DanesHammersmith Campus






BibTex format

author = {Bush, WS and McCauley, JL and DeJager, PL and Dudek, SM and Hafler, DA and Gibson, RA and Matthews, PM and Kappos, L and Naegelin, Y and Polman, CH and Hauser, SL and Oksenberg, J and Haines, JL and Ritchie, MD},
doi = {10.1038/gene.2011.3},
journal = {Genes and Immunity},
pages = {335--340},
title = {A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility},
url = {},
volume = {12},
year = {2011}

RIS format (EndNote, RefMan)

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=5.2E−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.
AU - Bush,WS
AU - McCauley,JL
AU - DeJager,PL
AU - Dudek,SM
AU - Hafler,DA
AU - Gibson,RA
AU - Matthews,PM
AU - Kappos,L
AU - Naegelin,Y
AU - Polman,CH
AU - Hauser,SL
AU - Oksenberg,J
AU - Haines,JL
AU - Ritchie,MD
DO - 10.1038/gene.2011.3
EP - 340
PY - 2011///
SN - 1466-4879
SP - 335
TI - A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility
T2 - Genes and Immunity
UR -
UR -
UR -
VL - 12
ER -