Within complex diseases like T2D and obesity, several genome-wide hits has been established as true associations. I know that there have been several attempts to locate the functional variation by fine-mapping the surrounding regions by genotyping Hapmap SNPs (+/-200kb) or sequencing of the locus.
Analysis of such data normally ends up with conditional analysis by making association study of the novel SNP and then condition on the lead SNP.
My Qs is: How do we establish whether we have found a true independent hit? or how do we establish that a novel SNP explains the association seen for the lead SNP?
We have done a lot of these conditional analysis and several times we see that surrounding interesting SNPs (ex a missense) gets more significant when conditioning on the lead SNP. Ex p-values going from 10-3 to 10-4. But is this just coincidence? can we make some power calculations? or what to do.
My concern is that these kind of studies gets very subjective when conclusion are made.
OK... that was a lot of Qs. In general I would like to hear if anyone has experience with conditional analysis of SNPs and how they interpret these results... Or even better; if you have another way of approaching this area.
Thanks for any kind of contribution!
All the best Thomas