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

Gene model association of rs13414207 with Multiple Sclerosis.

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

SNPs within <i>MERTK</i> define both risk and protective haplotypes associated with MS susceptibility.

<p>28 SNPs within the <i>MERTK</i> gene form a single block of very high LD (D'>0.99, LOD≥2). The five most frequent haplotypes (population frequency >1%) are shown in this schematic, along with the <i>p</i>-value of association of each haplotype with MS susceptibility as determined using a Chi-square test. Arrowhead indicates the haplotype-tagging allele of rs13414207 in haplotype 5. The alleles presented for rs17174870 are inferred from data obtained from sequencing the opposite strand but are presented as CT to maintain consistency with the remainder of the study.</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

The haplotype structure of variants identified in <i>MERTK</i>.

<p>The 52 variants in <i>MERTK</i> genotyped for association with MS susceptibility fall into 4 separate blocks. Haplotype blocks are connected with thick lines if connections are observed in >10% samples and thin lines if connections are observed in >1% samples. A schematic of the <i>MERTK</i> gene is shown underneath indicating the relationship of the blocks to the physical structure of <i>MERTK</i>. The haplotypes coloured in red are significantly associated with MS susceptibility (p<0.05) and the haplotype coloured in blue is associated with protection (p<0.05). The <i>p</i>-value of association was determined using a Chi-square test. #This variant represents a tri-nucleotide in-del (T/- = TGG; -)</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

Summary of variants identified in <i>MERTK</i>.

<p>Summary of variants identified in <i>MERTK</i>.</p

Individuals used for resequencing of <i>MERTK</i>.

<p>Individuals used for resequencing of <i>MERTK</i>.</p