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=5.2E-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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37232-0700, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Bush
authors.forename: J L
authors.initials: JL
authors.lastname: McCauley
authors.forename: P L
authors.initials: PL
authors.lastname: DeJager
authors.forename: S M
authors.initials: SM
authors.lastname: Dudek
authors.forename: D A
authors.initials: DA
authors.lastname: Hafler
authors.forename: R A
authors.initials: RA
authors.lastname: Gibson
authors.forename: P M
authors.initials: PM
authors.lastname: Matthews
authors.forename: L
authors.initials: L
authors.lastname: Kappos
authors.forename: Y
authors.initials: Y
authors.lastname: Naegelin
authors.forename: C H
authors.initials: CH
authors.lastname: Polman
authors.forename: S L
authors.initials: SL
authors.lastname: Hauser
authors.forename: J
authors.initials: J
authors.lastname: Oksenberg
authors.forename: J L
authors.initials: JL
authors.lastname: Haines
authors.forename: M D
authors.initials: MD
authors.lastname: Ritchie
mesh_terms: D002118:Calcium / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility; D004843:Epistasis, Genetic; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002118:Calcium