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

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.

[1]  M. Vitale,et al.  Human Platelets Contain Scinderin, a Ca2+-Dependent Actin Filament-Severing Protein , 1992, Thrombosis and Haemostasis.

[2]  N. Schork,et al.  Pathway analysis of seven common diseases assessed by genome-wide association. , 2008, Genomics.

[3]  T. Speed,et al.  Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians , 2008, Genes and Immunity.

[4]  N. Wilczak,et al.  Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors , 1999, Neurology.

[5]  James Wason,et al.  Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor , 2009, European Journal of Human Genetics.

[6]  G. Gallo.  Myosin II activity is required for severing-induced axon retraction in vitro , 2004, Experimental Neurology.

[7]  J. Divers,et al.  Susceptibility genes in common complex kidney disease , 2010, Current opinion in nephrology and hypertension.

[8]  S. Ryu,et al.  Phospholipase C isozymes selectively couple to specific neurotransmitter receptors , 1997, Nature.

[9]  Pablo Villoslada,et al.  Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. , 2006, Human molecular genetics.

[10]  R. Gold,et al.  Variation in the IL7RA and IL2RA genes in German multiple sclerosis patients. , 2009, Journal of autoimmunity.

[11]  L. Penrose,et al.  THE CORRELATION BETWEEN RELATIVES ON THE SUPPOSITION OF MENDELIAN INHERITANCE , 2022 .

[12]  S. Gabriel,et al.  Risk alleles for multiple sclerosis identified by a genomewide study. , 2007, The New England journal of medicine.

[13]  C. Wijmenga,et al.  Using genome‐wide pathway analysis to unravel the etiology of complex diseases , 2009, Genetic epidemiology.

[14]  Thomas Liedtke,et al.  Brain-specific splicing of alpha-actinin 1 (ACTN1) mRNA. , 2002, Biochemical and biophysical research communications.

[15]  M. Marcu,et al.  Scinderin, a Ca2+-Dependent Actin Filament Severing Protein that Controls Cortical Actin Network Dynamics During Secretion , 2004, Neurochemical Research.

[16]  T. Kataoka,et al.  Multiple roles of phosphoinositide-specific phospholipase C isozymes. , 2008, BMB reports.

[17]  G. Mills,et al.  Increase in cytosolic free calcium concentration is an intracellular messenger for the production of interleukin 2 but not for expression of the interleukin 2 receptor. , 1985, Journal of immunology.

[18]  María M. Abad-Grau,et al.  IL2RA/CD25 Gene Polymorphisms: Uneven Association with Multiple Sclerosis (MS) and Type 1 Diabetes (T1D) , 2009, PloS one.

[19]  Lin Chen,et al.  Susceptibility to glaucoma: differential comparison of the astrocyte transcriptome from glaucomatous African American and Caucasian American donors , 2008, Genome Biology.

[20]  Heather J Cordell,et al.  Case/pseudocontrol analysis in genetic association studies: A unified framework for detection of genotype and haplotype associations, gene‐gene and gene‐environment interactions, and parent‐of‐origin effects , 2004, Genetic epidemiology.

[21]  Tamara S Fraley,et al.  Phosphoinositide binding regulates alpha-actinin dynamics: mechanism for modulating cytoskeletal remodeling. , 2005, The Journal of biological chemistry.

[22]  Elizabeth A. Heron,et al.  The SNP ratio test: pathway analysis of genome-wide association datasets , 2009, Bioinform..

[23]  K. Suzuki,et al.  Tissue- and cell type-specific expression of mRNAs for four types of inositol phospholipid-specific phospholipase C. , 1989, Biochemical and biophysical research communications.

[24]  J. Stull,et al.  Quantitative measurements of Ca2+/calmodulin binding and activation of myosin light chain kinase in cells , 2004, FEBS letters.

[25]  A. Lalwani,et al.  Clinical and molecular genetic analysis of a family with macrothrombocytopenia and early onset sensorineural hearing loss. , 2009, European journal of medical genetics.

[26]  P. Donnelly,et al.  Genome-wide strategies for detecting multiple loci that influence complex diseases , 2005, Nature Genetics.

[27]  R. Fisher.  XV.—The Correlation between Relatives on the Supposition of Mendelian Inheritance. , 1919, Transactions of the Royal Society of Edinburgh.

[28]  Casey S. Greene,et al.  Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture , 2009, PloS one.

[29]  Marylyn D. Ritchie,et al.  Biofilter: A Knowledge-Integration System for the Multi-Locus Analysis of Genome-Wide Association Studies , 2008, Pacific Symposium on Biocomputing.

[30]  J. Schmidt,et al.  Myosin light chain kinase: expression in neurons and upregulation during axon regeneration. , 1996, Journal of neurobiology.

[31]  P. Matthews,et al.  Pathway and network-based analysis of genome-wide association studies in multiple sclerosis , 2009, Human molecular genetics.

[32]  H. Cordell.  Detecting gene–gene interactions that underlie human diseases , 2009, Nature Reviews Genetics.

[33]  Momiao Xiong,et al.  Gene and pathway-based second-wave analysis of genome-wide association studies , 2010, European Journal of Human Genetics.

[34]  I. Lavon,et al.  Anti-inflammatory properties of cholinergic up-regulation: A new role for acetylcholinesterase inhibitors , 2006, Neuropharmacology.

[35]  K. Timms,et al.  A unique isoform of phospholipase Cbeta4 highly expressed in the cerebellum and eye. , 1999, Biochimica et biophysica acta.

[36]  Silke Schmidt,et al.  Interleukin 7 receptor α chain ( IL7R ) shows allelic and functional association with multiple sclerosis , 2007, Nature Genetics.

[37]  Ludwig Kappos,et al.  Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci , 2009, Nature Genetics.

[38]  Gary E. Swan,et al.  Systematic biological prioritization after a genome-wide association study: an application to nicotine dependence , 2008, Bioinform..

[39]  Stephan Beck,et al.  A second major histocompatibility complex susceptibility locus for multiple sclerosis , 2007, Annals of neurology.