One thing we’re worried about is cases where the haplotypes have the small additive effects rather than individual SNPs, and you get an unpredictable (potentially deleterious) effect if you edit to a rare haplotype even if all SNPs involved are common.
This is a point of uncertainty that bothered me when I was doing a similar analysis a while ago. GWAS data is possibly good enough to estimate causal effects of haplotypes, but that’s not enough information to do single base edits. To have reasonable confidence of getting the predicted effect, it’d be necessary to to make all the edits to transform the original haplotype into a different haplotype.
And unlike with distant variants where additive effects dominate, it’d make sense if non-additive effects are strong locally, since the variants are near each other. Whether this is actually true in reality is way beyond my knowledge, though.
This is a point of uncertainty that bothered me when I was doing a similar analysis a while ago. GWAS data is possibly good enough to estimate causal effects of haplotypes, but that’s not enough information to do single base edits. To have reasonable confidence of getting the predicted effect, it’d be necessary to to make all the edits to transform the original haplotype into a different haplotype.
And unlike with distant variants where additive effects dominate, it’d make sense if non-additive effects are strong locally, since the variants are near each other. Whether this is actually true in reality is way beyond my knowledge, though.