Loss-of-Function genetic variants in muscle specific genes

In collaboration with the company Regeneron, we have sequence ~10.000 exomes from the Botnia family study, Finland (was finished spring 2018). We now aim to leverage this exome sequence data and examine individuals carrying loss of function (LoF) variants in genes with muscle specific expression, focusing on genes regulating metabolism. The rational for focusing on genes only expressed in skeletal muscle is that the protein/s these genes encode should also have a function specifically in muscle. Such genes should be excellent pharmacological targets, as chronic inhibition (i.e. LoF) would be well-tolerated in humans. The optimal target would be a gene with increased activity associated with insulin resistance and T2D, where the LoF-variant is well-tolerated and propagate a protective effect. We have identified 987 individuals carrying LoF-variants in 10 genes exclusively expressed in muscle and are currently investigating 3 of these candidates.