Common and low frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status

G. Gibson; M.D. Binder; A.D. Fox; D. Merlo; L.J. Johnson; L. Giuffrida; S.E. Calvert; R. Akkermann; G.Z.M. Ma; A.A. Perera; M.M. Gresle; L. Laverick; G. Foo; M.J. Fabis-Pedrini; T. Spelman; M.A. Jordan; A.G. Baxter; S. Foote; H. Butzkueven; T.J. Kilpatrick; J. Field; A.G. Kermode

doi:10.1371/journal.pgen.1005853

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Common and low frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status

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Common and low frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status

G. Gibson, M.D. Binder, A.D. Fox, D. Merlo, L.J. Johnson, L. Giuffrida, S.E. Calvert, R. Akkermann, G.Z.M. Ma, A.A. Perera, …

PLoS Genetics, Vol.12(3)

2016

DOI: https://doi.org/10.1371/journal.pgen.1005853

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Abstract

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.

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Title: Common and low frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status
Authors/Creators: G. Gibson (Author/Creator)
M.D. Binder (Author/Creator) - The University of Melbourne
A.D. Fox (Author/Creator) - Florey Institute of Neuroscience and Mental Health
D. Merlo (Author/Creator) - The University of Melbourne
L.J. Johnson (Author/Creator) - Florey Institute of Neuroscience and Mental Health
L. Giuffrida (Author/Creator) - The University of Melbourne
S.E. Calvert (Author/Creator) - Florey Institute of Neuroscience and Mental Health
R. Akkermann (Author/Creator) - The University of Melbourne
G.Z.M. Ma (Author/Creator) - The University of Melbourne
A.A. Perera (Author/Creator) - Florey Institute of Neuroscience and Mental Health
M.M. Gresle (Author/Creator) - The University of Melbourne
L. Laverick (Author/Creator) - The University of Melbourne
G. Foo (Author/Creator) - The University of Melbourne
M.J. Fabis-Pedrini (Author/Creator) - Perron Institute for Neurological and Translational Science
T. Spelman (Author/Creator) - The University of Melbourne
M.A. Jordan (Author/Creator) - James Cook University
A.G. Baxter (Author/Creator) - James Cook University
S. Foote (Author/Creator) - Australian National University
H. Butzkueven (Author/Creator) - The University of Melbourne
T.J. Kilpatrick (Author/Creator) - The University of Melbourne
J. Field (Author/Creator) - The University of Melbourne
A.G. Kermode (Author/Creator)
Publication Details: PLoS Genetics, Vol.12(3)
Publisher: Public Library of Science
Identifiers: 991005542388307891
Copyright: © 2016 Binder et al.
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article
Additional Information: Alan Kermode appears as part of the ANZGene Consortium

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.203 Neuromuscular Disorders; 1.203.147 Multiple Sclerosis
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics