A fascinating epistasis between a missense variant and stop gain variant in ACTN3

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Came across a fascinating finding in this recent GWAS where the association of a missense variant in ACTN3 gets eliminated by a truncating variant that lies upstream of missense variant. nature.com/articles/s41588-022-01165-1

A protein truncating variant Arg577Ter in ACTN3, seen in almost half the human population, has an interesting story of its own. See below thread. twitter.com/doctorveera/status/1362505568204783616?s=20&t=R8qQWtBpzTg1SmtSItAaGg

Though here the authors didn't find strong association for this PTV with their phenotype (sedentary behavior, physical activity), they found a significant association with a missense variant (Glu635Ala) that lies downstream of the PTV (Arg577Ter)

In individuals carrying the PTV, this missense variant cannot have a phenotypic effect as it lies downstream of the truncation site and so will be chopped off from the protein.

The authors show that using a haplotype analysis. The effect allele C of the missense variant shows association only in the absence of PTV (C allele) but not in the presence of PTV (T allele) Very cool!

A nice example of a natural experiment of removing a genetic variant from the gene to test if it eliminates the phenotypic association.