# Titin-Truncating variants predispose to dilated cardiomyopathy in populations genetically similar to african and european reference populations

## TL;DR

TTN gene variants increase heart disease risk similarly in people with genetic backgrounds similar to African and European populations.

## Contribution

Demonstrates consistent TTN variant effects on DCM risk across diverse genetic backgrounds, challenging ancestry-based assumptions.

## Key findings

- TTN truncating variants significantly increase DCM risk in both European and African genetically similar populations.
- No significant difference in TTN variant effect across fractions of similarity to African reference populations.
- TTN variants also associate with atrial fibrillation and reduced heart function across diverse groups.

## Abstract

The 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. To determine the effect of TTNtvs on cardiovascular disease risk, we leveraged whole exome sequencing and electronic health record data from 43,731 Penn Medicine Biobank (PMBB) participants recruited from across the Penn Medicine healthcare system. Fraction of genetic similarity to the 1000 Genomes Project (1000G) African (AFR) reference population was determined using ADMIXTURE analysis. Logistic regression was performed to evaluate the association of hiPSI TTNtvs with prevalent DCM and atrial fibrillation (Afib), and linear regression was used to evaluate the association with reduced left ventricular ejection fraction (LVEF) either using dichotomized genetically similar population subgroup analysis or integrating ADMIXTURE population fraction. 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 (EUR) reference population (OR=6.12, 95% confidence intervals [CI] 4.33 to 8.65, P < 0.001) and individuals genetically similar to the AFR reference population (OR=3.44, 95% CI 1.97 to 5.99, P < 0.001). These results were consistent when considering the effect of change in fraction of similarity to the African reference population by ADMIXTURE as a continuous variable. Similar results were observed for the effect of TTNtvs on Afib and LVEF. Our findings demonstrate that TTNtvs are associated with increased risk of DCM, reduced LVEF, and Afib among a diverse cohort. There is no significant difference in effect of TTNtvs across fractions of similarity to the AFR reference population suggesting genetic background should not be considered when screening individuals for titin-related cardiovascular disease.

Variants in several different genes have been identified as causal changes that predispose individuals to cardiovascular disease. Within the context of dilated cardiomyopathy (DCM), variants in the TTN gene (the gene that encodes the Titin protein which is the largest protein in the human body) are the most well-known genetic changes that contribute to an individual’s risk of DCM. However, investigations into the effect of TTN variants have suggested that there is a smaller effect among individuals genetically similar to the African reference populations. This has led some to consider how ancestry may impact the risk conferred by variants in TTN. However, more recently evidence has suggested that the discrepancy observed between different ancestries is related more to sample size and that most studies of genetic risk factors for DCM have been carried out in largely homogenous populations consisting primarily of individuals genetically similar to European reference populations. Here we observe that the effects of variants in TTN are similar across populations genetically similar to European and African reference populations either when individuals are dichotomized by population subgroup similarity or when genetic similarity is considered as a continuous variable.