A Phenome-Wide Association Study of Drugs and Comorbidities Associated With Gastrointestinal Dysfunction in Systemic Sclerosis

. Objective. To explore the causes of and contributors to gastrointestinal (GI) dysfunction in systemic sclerosis (SSc) in a phenome-wide association study (PheWAS), using real-world clinical records data. Methods. Twelve thousand five hundred thirty-five documented clinical assessments of 2058 consenting individuals with SSc at the Royal Free Hospital (UK) were available for detailed phenotyping. Diagnoses and drugs were mapped to structured dictionaries of terms (Disease Ontology project and DrugBank Open Data, respectively). A PheWAS model was used to explore links between 6 important SSc-GI domains (constipation, diarrhea, dysmotility, incontinence, gastroesophageal reflux, and small intestinal bacterial overgrowth [SIB O]) and exposure to various comorbidities and drugs. Hits from the PheWAS model were confirmed and explored in a subcohort reporting quantitative GI symptom scores from the University of Results. One thousand five hundred forty-six individuals were entered into the PheWAS analysis. Six hundred seventy-three distinct diagnoses and 634 distinct drugs were identified in the dataset, as well as SSc-specific phenotypes such as antinuclear antibodies (ANA). PheWAS analysis revealed associations between drugs, diagnoses, and ANAs with 6 important SSc-GI outcomes: constipation, diarrhea, dysmotility, incontinence, reflux, and SIBO. Subsequently, using GIT 2.0 symptom scores links with SSc-GI were confirmed for 22 drugs, 4 diagnoses, and 3 ANAs. Conclusion. Using a hypothesis-free PheWAS approach, we replicated known, and revealed potential novel, risk factors for SSc-GI dysfunction, including drug classes such as opioid, antimuscarinic, and endothelin receptor antagonist, and ANA subgroup.

Automated summary

In this phenome-wide association study (PheWAS), we investigated the causes and contributors to gastrointestinal dysfunction in systemic sclerosis (SSc) using clinical records data. We found associations between drugs, diagnoses, and antinuclear antibodies (ANA) with important SSc-GI outcomes such as constipation, diarrhea, and gastroesophageal reflux. Our study also identified potential novel risk factors for SSc-GI dysfunction.