Thank you!

We hope this approach will enable others to search for (and perhaps find!) epistatic effects in cis, and through this to learn more about the genetic basis of complex phenotypes.

Thanks for reading! (end 🧵)

In contrast, our method only requires publicly available WGS data for samples of similar ancestral background (we use 1KGP) whose information is efficiently encoded in the form of an ARG. This makes it applicable in settings where WGS data is not available (including for non-human species).

it was very difficult to rigorously test for such effects.

WGS data or dense imputation panels allowed for checking whether any neighbouring variant accounted for a putative interaction but only if this data was available for the same sample in which the epistasis testing was done.

evidence *against* the existence of a problematic variant.

This allows us to quantify the observed evidence either for or against a potential interaction being real.

Epistasis between variants in cis could be common (or at least less rare than that between variants farther apart) but until now...

the genealogy (in the form of an ARG).

We first derive the conditions that a problematic variant would have to satisfy to yield a significant interaction in the first place. We then look for clades within the ARG that might harbour such a variant or, conversely, for clades that provide...

But (by definition) we don't observe the possible hidden variants that might be driving the putative interaction. So how can we test for the existence of a variant that we don't see?

In the paper, we derive tests for whether phantom epistasis is likely to arise between two variants due to...

effect of a third, unobserved variant. This has been called "phantom epistasis" and, far from being a theoretical issue, has led to the retraction of a high-profile paper.
www.nature.com/articles/s41...

Given a potential interaction, we would like to know if it might be a "phantom" effect...

Genetic interactions are hard to find, and very few have been identified for humans. One challenge to their detection is that we can't reliably test for interactions between neighbouring variants: if we see that two variants in LD interact, their interaction may actually be tagging the *additive*...

Epistasis happens when two genetic variants have a combined effect on a phenotype that is different (greater or lesser) than the sum of their effects when present in isolation: the whole is more (or less) than the sum of its parts. See this great thread for an overview:
bsky.app/profile/sash...

Beautiful figures and slides!

a generous stipend (+ a 50k research grant!) and choose their own supervisor from among a long list of amazing researchers, and all this in Oxford.

If you know of anyone interested in doing a PhD in genetics, encourage them to apply!