#apaperaday: A genome-wide association analysis of loss of ambulation in dystrophinopathy patients suggests multiple candidate modifiers of disease severity

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: A genome-wide association analysis of loss of ambulation in dystrophinopathy patients suggests multiple candidate modifiers of disease severity

It is from the European Journal of Human Genetics by Kevin Flanigan et al on a genome wide association study in Duchenne patients to find disease modifiers. Doi 10.1038/s41431-023-01329-5.

Duchenne and Becker are caused by dystrophin mutations. The main determinant of severity of progression is whether dystrophin proteins can be produced or not: frame disrupting mutations cause severe Duchenne, frame maintaining mutations cause less severe Becker.

However there are also other factors that play a role within Duchenne and Becker disease progression such as gene variations in genes encoding proteins involved in inflammation fibrosis regeneration and muscle membrane repair. Finding such genes can be done with genome wide association studies where you check for different regions if variations correlate with e.g. loss of ambulation age. Challenge: for this you need large numbers of patients. Duchenne and Becker are rare diseases…

Here authors did the largest GWAS for Duchenne so far with 419 patients (which is small for GWAS but large for Duchenne). Authors tried to improve sensitivity by excluding all patients expected to produce some dystrophin and through adapting statistics for small cohorts.

Authors did not find any of previously identified genetic modifiers such as LTBP4. They did find multiple candidate regions (96 SNPs) where they followed up 6 loci that had highest likelihood. For 2 genes (ETAA1 and PADD6G) it was found they were involved in regeneration.

Both genes encode proteins that are involved in satellite cell proliferation and polarity (making sure a satellite cell returns back to stem cell state). Authors did not do functional or confirmatory studies but argue that these genes “make sense” as modifiers.

In the discussion authors argue their findings support the idea that many pathways are involved in Duchenne pathology and thus many modifiers exist. This makes finding them challenging and replication studies difficult as environment and racial backgrounds influence as well.

Eg some variations may only be present in some races and not others. Sadly most GWAS studies are done on Caucasians for Duchenne…The many pathways also means therapeutic approaches are challenging as they affect only a little bit of the whole (except for dystrophin restoration).

While authors do not show functional data or confirmatory studies I appreciate them publishing the work so others can build on it now rather than many years down the line while authors work on confirming!