Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with multiple sclerosis susceptibility

Abstract

Multiple sclerosis (MS) is a debilitating, chronic demyelinating disease of the central nervous system affecting over 2 million people worldwide. The TAM family of receptor tyrosine kinases (TYRO3, AXL and MERTK) have been implicated as important players during demyelination in both animal models of MS and in the human disease. We therefore conducted an association study to identify single nucleotide polymorphisms (SNPs) within genes encoding the TAM receptors and their ligands associated with MS. Analysis of genotype data from a genome-wide association study which consisted of 1618 MS cases and 3413 healthy controls conducted by the Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene) revealed several SNPs within the MERTK gene (Chromosome 2q14.1, Accession Number NG_011607.1) that showed suggestive association with MS. We therefore interrogated 28 SNPs in MERTK in an independent replication cohort of 1140 MS cases and 1140 healthy controls. We found 12 SNPs that replicated, with 7 SNPs showing p-values of less than 10(-5) when the discovery and replication cohorts were combined. All 12 replicated SNPs were in strong linkage disequilibrium with each other. In combination, these data suggest the MERTK gene is a novel risk gene for MS susceptibility.

Figure 1. Location of SNPs within the MERTK gene.

A. Schematic of the MERTK gene (Accession Number NG_011607.1, Chromosome 2: 12,656,056-112,787,138 forward strand). Black rectangles indicate the 19 exons of MERTK and grey lines show physical location of the 12 replicated SNPs. B. Linkage disequilibrium (LD) structure for all Hapmap phase II CEU SNPs (release 24, build 36, forward strand) in the MERTK gene, visualized using Haploview v4.2 (ref. 29). Lines point out the 12 replicated SNPs. Inter-SNP LD is represented by shaded squares, with red shading indicating strongest LD (D′ = 1), and white indicating weak or no LD between SNPs.