However, the fact that additivity is... fine... for discovery, and probably also out of sample population assessment (PRS etc) doesn't mean it is good for everything we want to do.
Replies
Sort of obviously in rare disease diagnosis - where you want v v low false positives and you are conditioning on the alleles in one person, you don't just say "oh it will be fine to use an additive model" - obviously you take into account dominance/recessive if present;
aug 28, 2025, 3:10 pm • 0 0 • view
Furthermore you will take into account GxE, though this is complex because we rarely know these terms - this looks like variable penetrance to us.
aug 28, 2025, 3:10 pm • 1 0 • view
Interestingly in our own work on common variants to OCT based retinal phenotypes we could see some evidence of 2 loci GxG and also association with a rare gene locus with variable penetrance journals.plos.org/plosgenetics...
aug 28, 2025, 3:10 pm • 0 0 • view
Another aspect is that we often use additive parameters, eg, the slope of the association, often called beta, in meta-analysis or other analyses, such as Mendelian Randomisation. The assumption is that this slope (beta) is well estimated and slope by GWAS
aug 28, 2025, 3:10 pm • 0 0 • view
However, in the scenario of overdominance (the hetrezygote mean is above or below one of the homozygote means) - impossible to get for additive models - the additive beta estimate becomes an unstable, frequency dependent parameter. This is ... not healthy for on-going analysis.
aug 28, 2025, 3:10 pm • 0 0 • view
Finally of course discovering GxE effects gives us new insights into environmental impacts - and sometimes those environmental impacts are easier to change than the genetic basis of course (eg, stopping smoking, or stopping drinking)
aug 28, 2025, 3:10 pm • 1 0 • view
Similarly discovering 2-loci GxG effects - which are as rare as hen's teeth in human GWAS (though see above on our OCT study) shows us new biology; like all genetics, low variance of genetic variants does not imply low impact if drugged (cf statins and HMG-CoA Reductase)
aug 28, 2025, 3:10 pm • 2 0 • view
The medaka paper was a tour de force lead by two great students: @saulpierotti.bsky.social in my research group and Bettina Welz in @wittbrodtlab.bsky.social's group.
aug 28, 2025, 3:10 pm • 1 0 • view