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. 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

A new mouse model of Canavan leukodystrophy displays hearing impairment due to central nervous system dysmyelination

Canavan disease is a leukodystrophy caused by mutations in the ASPA gene. This gene encodes the enzyme that converts N-acetylaspartate into acetate and aspartic acid. In Canavan disease, spongiform encephalopathy of the brain causes progressive mental retardation, motor deficit and death. We have isolated a mouse with a novel ethylnitrosourea-induced mutation in Aspa. This mutant, named deaf14, carries a c.516T>A mutation that is predicted to cause a p.Y172X protein truncation. No full-length ASPA protein is produced in deaf14 brain and there is extensive spongy degeneration. Interestingly, we found that deaf14 mice have an attenuated startle in response to loud noise. The first auditory brainstem response peak has normal latency and amplitude but peaks II, III, IV and V have increased latency and decreased amplitude in deaf14 mice. Our work reveals a hitherto unappreciated pathology in a mouse model of Canavan disease, implying that auditory brainstem response testing could be used in diagnosis and to monitor the progression of this disease

Gene model association of rs13414207 with Multiple Sclerosis.

<p>Gene model association of rs13414207 with Multiple Sclerosis.</p

Top 10 SNPs within <i>MERTK</i> associated with Multiple Sclerosis susceptibility.

<p>Top 10 SNPs within <i>MERTK</i> associated with Multiple Sclerosis susceptibility.</p

Discordant effect of rs7422195 in the presence or absence of <i>HLA-DRB1*15</i>:<i>01</i>.

<p>All samples (n = 3000) were first stratified according to the number of <i>DR15</i> alleles then by genotype at rs7422195. (A) The frequency of the A-allele of rs7422195 was calculated for cases and controls within each <i>DR15</i> genotype group, showing a clear decrease in the frequency of the A-allele with increasing copies of <i>DR15</i> within MS cases, and the opposite effect in healthy controls. The total number of samples within each <i>DR15</i> genotype group is included below the group name on the x-axis, with the number of individuals used to calculate each point represented in brackets on the graph. (B) Disease frequency for each group was calculated as the number of MS cases divided by the total number of cases and healthy controls for each genotype. The minor allele at rs7422195 shows an increase in the disease risk in the absence of <i>DR15</i>, but a clear decrease in the disease frequency amongst individuals carrying two copies of <i>DR15</i>.</p

Heat map of variants found in <i>MERTK</i> grouped according to haplotype.

<p>The sequence of each group following resequencing was compared with the reference genome (GRCh37/hg19). Coloured lines indicate a base that is variant compared with the reference genome. Mapping of the groups shows that haplotype groups 3 and 4 were most closely related to the reference sequence, showing many invariant nucleotides. Conversely haplotype groups 2 and 5 showed the greatest differences to the reference sequence and an apparently close relationship, sharing many variants.</p

Results of the association testing for variants identified in <i>MERTK</i>.

<p>Results of the association testing for variants identified in <i>MERTK</i>.</p

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. 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.</p

Disease course is altered in the presence of <i>MERTK</i> susceptibility-associated variants.

<p>Individuals initially presenting with a relapsing-remitting course of MS were stratified by both <i>DR15</i> status and genotype at rs7422195. (A) In the presence of the minor (A) allele of rs7422195, <i>DR15</i> negative individuals (n = 370) showed a strong trend towards increased probability of progression (<i>p</i> = 0.07) (B) In the presence of the major (G) allele of rs7422195 <i>DR15</i> homozygous individuals (n = 68) showed a strong trend towards increased probability of progression (<i>p =</i> 0.081)</p