Titin-Truncating variants Predispose to Dilated Cardiomyopathy in Diverse Populations

ImportanceThe effect of high percentage spliced in (hiPSI) TTN truncating variants (TTNtvs) on risk of dilated cardiomyopathy (DCM) has historically been studied among population subgroups defined by genetic similarity to European reference populations. This has raised questions about the effect of TTNtvs in diverse populations, especially among individuals genetically similar to African reference populations. ObjectiveTo determine the effect of TTNtvs on risk of DCM in diverse population as measured by genetic distance (GD) in principal component (PC) space. DesignCohort study SettingPenn Medicine Biobank (PMBB) is a large, diverse biobank. ParticipantsParticipants were recruited from across the Penn Medicine healthcare system and volunteered to have their electronic health records linked to biospecimen data including DNA which has undergone whole exome sequencing. Main Outcomes and MeasuresRisk of DCM among individuals carrying a hiPSI TTNtv. ResultsCarrying a hiPSI TTNtv was associated with DCM among PMBB participants across a range of GD deciles from the 1000G European centroid; the effect estimates ranged from odds ratio (OR) = 3.29 (95% confidence interval [CI] 1.26 to 8.56) to OR = 9.39 (95% CI 3.82 to 23.13). When individuals were assigned to population subgroups based on genetic similarity to the 1000G reference populations, hiPSI TTNtvs conferred significant risk of DCM among those genetically similar to the 1000G European reference population (OR = 7.55, 95% CI 4.99 to 11.42, P<0.001) and individuals genetically similar to the 1000G African reference population (OR 3.50, 95% CI 1.48 to 8.24, P=0.004). Conclusions and RelevanceTTNtvs are associated with increased risk of DCM among a diverse cohort. There is no significant difference in effect of TTNtvs on DCM risk across deciles of GD from the 1000G European centroid, suggesting genetic background should not be considered when screening individuals for titin-related DCM. Key Points QuestionDo high percentage spliced in (hiPSI) titin truncating variants (TTNtvs) confer similar levels of risk for dilated cardiomyopathy (DCM) across diverse populations? FindingsIn a cohort study that comprised 43,731 individuals of diverse genetic background with electronic health records linked to whole exome sequencing data, hiPSI TTNtvs conferred increased risk of DCM across all individuals irrespective of genetic background as measured by genetic distance from the 1000 Genomes Project European centroid. MeaningThe findings of this study suggest that TTNtvs increase risk of DCM among individuals independent of genetic background and that genetic similarity to a reference population should not play a role in screening for genetic causes of dilated cardiomyopathy.