Dear Samra, , maybe what makes that region important is a change in regulatory regions instead of coding regions of the gene ... Maybe you can try to quantify expression of your candidate/s gene/s, between both kind of mice and see if there is a quantitative difference... if this makes sense with the gene' function... 

Remember that what you map through linkage analysis is the polymorphism.  When the polymorphism is in the coding region of the gene, the QTL should contain the gene responsible for the phenotype.  However, if the polymorphism is not in the coding region of the gene (and the previous responders suggest several ways in which noncoding polymorphisms could have functional effects) then it is possible that the polymorphism regulates a gene some distance away.

What about the methylation status surrounding this gene of interest, is it same in both cases? My guess would be that the methylation pattern won't be the same.

Thanks everyone for your input. Your experienced opinions have helped me to clarify my views.

Simran, I don't know about the methylation status as I haven't jumped into epigenetics yet but there was a recent paper from another group that stated demethylation of one of the genes' promoter and linked it to pathogenesis of RA in humans. I discussed it with my supervisor that we should check for the methylation of genes in the fragment but she thinks that linkage analysis is based on polymorphisms so we should stick to genetics.

I am just wondering if it is relevant to use epigenetics' approach in this case whereby my supervisor does not  agree to my thought.  

Remember, it always helps to know what you are talking about. How do you define a gene? A coding-gene? In my book there are protein-coding genes and non-protein coding genes. And very little of what is transmitted from one generation to the next is DNA. Much more of the chromosomes (which comprise what is transmitted, together with non-chromosomal material) is NOT DNA.

Excellent suggestions from everybody here. I agree with your supervisor that before jumping on epigenetic mechanisms, you first need to consider the genetic data in full. I have a few questions: 1) from you description is not clear if you did genome-wide interrogation or a targeted genotyping of your gene of interest; 2) if genome-wide how confident are you in this polymorphisms being the associated one, was it the only one, did you do any correction for multiple testing, I'd assume you did; 3) what kind of mice strains are you working with? Are these inbred, congenic or are from the heterogenous panel? This is important as the interpretation of the association data will differ.

If you working with heterogenous panel of mice strains I'd suggest that you determine the LD between your significant polymorphism and all other polymorphisms in the implicated region. The LD pattern will give a better idea whether this is the implicated gene or not. If that's the right SNP, you can test the expression of your gene contingent on genotype to see whether this SNP act as an eQTL for your gene. If so, that will increase your confidence in the gene.

You can check ENCODE database to see what's known about the genomic region of your SNP and the gene, if they have the relevant tissue or cell line of course. If you still want to explore the epigenetic angle you can use the ENCODE data to check out if your SNP is reported to affect methylation status. If so then you're in a stronger position to pursue the epigenetic aspect of your research. Hope it helps.

Dear Vladimir, thanks for your detailed comment. The linkage analysis was done years ago, so I don't know very fine details. It was a cross between two inbred mouse strains B10.RIII (that resembles C57BL/6 strain), which is susceptible to induced arthritis, and RIIIS/J strain, which is resistant to same stimulus. Linkage analysis identified QTL and I am working with congenic mice for one of these QTLs identified in that study. With further selection, the region is quite small now (1.8Mbp) and has 4 protein coding genes. My job is to identify candidate gene(s) for arthritis from the region.

While differential methylation could result in different susceptibility to disease, methylation alone is unlikely to explain a QTL as there is only limited evidence for transgenerational heritability of methylation. However, some SNPs have been shown to modulate methylation at nearby CpGs - termed methQTLS and this could be one mechanism by which non-coding SNPs may exert functional effects.