Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status

PLoS Genet. 2016 Mar 18;12(3):e1005853. doi: 10.1371/journal.pgen.1005853. eCollection 2016 Mar.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • HLA-DRB1 Chains / genetics*
  • Humans
  • Monocytes / metabolism
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / metabolism
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics*
  • Receptor Protein-Tyrosine Kinases / biosynthesis
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Risk Factors
  • c-Mer Tyrosine Kinase


  • HLA-DRB1 Chains
  • HLA-DRB1*15:01 antigen
  • Proto-Oncogene Proteins
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • c-Mer Tyrosine Kinase

Grants and funding

This work was supported by the National Multiple Sclerosis Society (US) Grant Number 6007629 to MDB, TJK, JF, HB and ADF; by the Multiple Sclerosis Research Australia Grant Number 13-013 to MDB, JF and TJK; by the National Health and Medical Research Council Grant Number APP1032486 to HB, JF and AGB, and by the Australian Research Council Linkage Grant Number LP110100473 to HB, JF abd AGB. The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.