Abstract 9872: Cardiac Enhancer Variants at the Mtss1 Locus Are Associated with Smaller, More Contractile Hearts

Abstract

Introduction: Variants at the MTSS1 locus influence cardiac structure, function, and failure in multiple genome wide association studies (GWAS), yet the genetic mechanisms remain unclear. We previously identified variants in a cardiac enhancer in cis to MTSS1 that influence expression in the human left ventricle (LV). Here we used bioinformatic approaches to determine if these variants explain the association between common MTSS1 variation and cardiac traits. We hypothesized that alleles that reduce MTSS1 expression are cardioprotective. Methods: To confirm a shared causal variant, we combined expression quantitative trait locus (eQTL) data from GTEx with GWAS from the UKBiobank (UKBB) using co-localization. GTEx consists of 386 LV samples with RNAseq. The UKBB is a prospective study of over 500,000 patients recruited from the United Kingdom with extensive genotype and phenotype data. We obtained relevant data as part of approved protocol 65965, using 82 additional quantified cardiac MRI (cMRI) traits from return dataset 2383. Genome association tests were performed at the MTSS1 locus (chr8:124550790-124728429) using Plink2.0; co-localization was performed with Coloc. Results: Co-localization analysis of 26,892 patients revealed 3 overlapping variants in the MTSS1 enhancer region significantly associated with LV expression of MTSS1 and multiple cMRI traits. These include LV ejection fraction (LVEF) (p=1.3 x 10 -10 ), LV end-systolic volume (p=1.2 x 10 -8 ), and global circumferential strain (p=1.1 x 10 -7 ). Variants that decrease MTSS1 expression are associated with decreased volumes, increased LVEF, and improved circumferential strain, consistent with smaller, more contractile hearts (see figure for detail). Conclusion: We utilize a bioinformatics approach to clarify genetic mechanisms by which a previously identified locus modulates cardiac traits. These results support a cardioprotective phenotype associated with reduced LV MTSS1 expression.