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

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. <i>MERTK</i> 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 <i>MERTK</i> 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 <i>MERTK</i> in monocytes and higher expression of <i>MERTK</i> was associated with either increased or decreased risk of developing MS, dependent upon <i>HLA-DRB1*15:01</i> 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 <i>MERTK</i> are associated with MS susceptibility, one of which has the potential to alter <i>MERTK</i> transcription, which in turn can alter both susceptibility and disease course in MS patients.