Titin-Truncating variants Predispose to Dilated Cardiomyopathy in Diverse Populations

Area of Science:

• Genetics and Genomics
• Cardiovascular Diseases
• Population Health

Background:

• The association between high percentage spliced in (hiPSI) TTN truncating variants (TTNtvs) and dilated cardiomyopathy (DCM) risk is primarily studied in European-ancestry populations.
• Limited data exists on TTNtv effects in diverse populations, particularly those genetically similar to African reference populations, hindering comprehensive risk assessment.

Purpose of the Study:

• To investigate the association between TTNtvs and DCM risk across diverse populations.
• To evaluate the influence of genetic distance (GD) from reference populations on TTNtv-associated DCM risk.

Main Methods:

• A cohort study was conducted using data from the Penn Medicine Biobank (PMBB), a large, diverse biobank.
• Whole exome sequencing data and electronic health records were analyzed for participants.
• Genetic similarity was assessed using principal component analysis relative to 1000 Genomes Project reference populations.

Main Results:

• hiPSI TTNtvs were significantly associated with increased DCM risk in the diverse PMBB cohort.
• Effect estimates for TTNtv-associated DCM risk remained consistent across deciles of genetic distance from the 1000G European centroid.
• Significant DCM risk was observed in subgroups genetically similar to both European (OR=7.55) and African (OR=3.50) reference populations.

Conclusions:

• TTNtvs are a significant risk factor for DCM across diverse ancestral backgrounds.
• The risk conferred by TTNtvs for DCM is not significantly modified by genetic background.
• These findings suggest that genetic background should not be a barrier to screening for titin-related DCM.