Genome Wide Association Study

Modified Project Summary/Abstract Section Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy. The disorder causes progressive muscle weakness, cognitive impairment, cardiac arrhythmias and early mortality. The basis for this disorder is a CTG repeat expansion in the 3’ untranslated region of the DMPK gene. The CTG repeat expansion is variable and roughly associated with disease severity in that shorter repeat expansions are generally associated with a later age of onset and longer repeat expansion are associated with an earlier age of onset. However, there is significant variability and prior evidence suggests repeat length alone does not predict overall disease onset and progression. Our group and others have identified, using a candidate gene approach that modifiers in DNA repair or replication pathways, such as DNA mismatch repair gene MSH3, modify disease severity. In parallel, early therapeutic trial results have suggested similarly matched individual may be variably responsive to therapies. This suggests genetic variants may be responsible for both modifying disease severity as well as therapeutic responsiveness in DM1. We hypothesize genetic modifiers in DNA repair or replication pathways or in RNA splicing proteins contribute to the variable age of onset and therapeutic responsiveness in DM1, when controlling for the repeat expansion length. The current study seeks to leverage six prior natural history studies that enrolled over 1600 individuals with DM1. We will perform a genome-wide association study to identify both common and rare variants associated with changes in disease severity (Aim 1). In this approach, we will use age of symptom onset as the primary phenotype. We will use whole genome sequencing to comprehensively capture genome-wide variants. We will use age of onset as the primary continuous phenotype and test for SNP associations using linear models that control for CTG repeat length effects as covariates. Other phenotypes will also be assessed as secondary phenotypes, including quantitative measures of muscle function, ambulation, and cognition, and dichotomous measures of respiratory and cardiac function. In Aim 2, we seek to perform a genome wide screen of therapeutic responsiveness using a cell system with a splicing reporter to model responsiveness to therapeutics similar to those in clinical trials now. We will then use available mouse models (HSALR and DMSXL) to model identified hits in the appropriate system. Completion of these Aims will identify genes that modify the disease severity and therapeutic responsiveness in DM1. Identification of these modifiers will improve our understanding of the genetic factors affecting CTG repeat stability, age of onset, and disease progression and appropriate trial design. Ultimately, these modifiers may serve as novel targets for therapeutic development.