Candidate gene modifiers of dystrophinopathy identified by the uniform application of genome-wide datasets to novel GWAS-identified loci
Flanigan, K. M.; Waldrop, M. A.; Martin, P. T.; Alles, R.; Dunn, D. M.; Alfano, L. N.; Simmons, T. R.; Moore-Clingenpeel, M.; Burian, J.; Seok, S.-C.; Vieland, V. J.; Weiss, R. B.
Show abstract
Although the major determinant of disease severity in patients with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether their dystrophin gene (DMD) mutation disrupts the mRNA reading frame or allows expression of a partially functional protein, other genes have been proposed or demonstrated to modify the severity of disease progression. In a companion paper to this one, we describe our novel approaches to genome-wide association study (GWAS) of loss of ambulation (LOA) in the largest genome-wide search to date for loci influencing disease severity in DMD patients. Candidate regulatory SNPs that modify disease progression were identified using an evidential statistical paradigm and here we present a uniform application of recent functional genomic datasets to explore the potential functional impact of the top six candidate regions with PPLD scores of [≥]0.4. The results of this analysis of the largest DMD GWAS survey to date elucidate recurrent and potentially new pathways for intervention in the dystrophinopathies.
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