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

William S. Bush | Zendy; Jacob L. McCauley | Zendy; Philip L. DeJager | Zendy; Scott Dudek | Zendy; D A Hafler | Zendy; Rachel A. Gibson | Zendy; Paul M. Matthews | Zendy; Ludwig Kappos | Zendy; Yvonne Naegelin | Zendy; Chris H. Polman | Zendy; Stephen L. Hauser | Zendy; Jorge R. Oksenberg | Zendy; Jonathan L. Haines | Zendy; Marylyn D. Ritchie | Zendy

Open Access

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

Author(s) -

William S. Bush,

Jacob L. McCauley,

Philip L. DeJager,

Scott Dudek,

D A Hafler,

Rachel A. Gibson,

Paul M. Matthews,

Ludwig Kappos,

Yvonne Naegelin,

Chris H. Polman,

Stephen L. Hauser,

Jorge R. Oksenberg,

Jonathan L. Haines,

Marylyn D. Ritchie

Publication year - 2011

Publication title -

genes and immunity

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.35

H-Index - 100

eISSN - 1476-5470

pISSN - 1466-4879

DOI - 10.1038/gene.2011.3

Subject(s) - biology , genome wide association study , epistasis , gene , gene interaction , genetics , computational biology , single nucleotide polymorphism , genotype

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.

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