RE: Covariate models of genetic polymorphisms

From: Mark Sale - Next Level Solutions mark@nextlevelsolns.com Subject: RE: [NMusers] Covariate models of genetic polymorphisms Date: Fri, 07 Jul 2006 09:16:49 -0700 Bill, Lai San Tham As you seem to suspect, genetic markers (and IMHO many covariates) frequently exert their effect only when present in combinations. So, Bill is correct that the interaction between the genes ought to be tested, as in Bill code GRPCL=POP_CL*SizeDescriptor+FGene1+FGene2*FGene1 It is entirely possible that you would find that FGene1, FGene2 etc individually have little to no effect. However, if you put in GRPCL=POP_CL*SizeDescriptor+FGene1*FGen2 ; if gene1 and gene2 need to be mutant or perhaps GRPCL=POP_CL*SizeDescriptor+FGene1*(1-FGen2) ; if gene1 is to be mutant and gene2 wild type or perhaps GRPCL=POP_CL*SizeDescriptor+(1-FGene1)*FGene2 etc etc you might find a very important effect. An effect is seen only when Gene1 and Gene2 are both mutants, but having a wild type Gene1 compensates for a mutant Gene1, with no effect on the phenotype. That is, the effects are not independent, but very dependent. Testing each efffect individually is likely not adequate. However, the number of combination of even a modest number of genes, with only 2 or 3 polymorph very quickly becomes prohibitively large. Even in the model that Bill proposed, I'd be concerned that it was over parameterized and would have convergence problems if all the effects were put in together, rather than the usual method of one at a time. I'm not sure if this is what you mean by cross-talk, perhaps it is this sort of interaction. I usually think of cross talk (in biology at least) as activation/inhibition of one receptor by some activity of another receptor, even though they aren't heterodimers. This receptor cross talk can be mediated by changes in gene expression, but I haven't heard the term cross talk used when refering to polymorphisms. Those who read this list server already know about my proposed solution, so I won't bore them with that again. Mark Sale MD Next Level Solutions, LLC www.NextLevelSolns.com