Furthermore you will take into account GxE, though this is complex because we rarely know these terms - this looks like variable penetrance to us.
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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...
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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
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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.
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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)
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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)
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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.
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