Human and zebrafish data corroborate gene x gene interactions in ameliorating Duchenne muscular dystrophy disease progression

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder involving progressive muscle tissue loss with replacement by fat and fibrotic tissue, leading in most cases to loss of ambulation (LOA) by early to mid-adolescence. We have previously reported the largest DMD genome-wide analysis to date, using N = 419 patients from the United Dystrophinopathy Project (UDP) whose primary DMD mutations are presumed to preclude production of residual dystrophin. We found strong evidence for 6 modifiers of LOA, 4 of which have been validated in zebrafish. Here we follow up by investigating possible gene-gene interactions both in the UDP and in zebrafish. We find strong evidence of interaction effects for 6 gene pairs in the UDP. We were able to test for interaction in zebrafish for one of these pairs, MAN1A1 and ACTN3, finding strong evidence of an interaction effect with apparent rescue of muscle organization to nearly wild-type levels.