Rare coding TTN variants are associated with electrocardiographic QT interval in the general population.
We have shown previously that noncoding variants mapping around a specific set of 170 genes encoding cardiomyocyte intercalated disc (ID) proteins are more enriched for associations with QT interval than observed for genome-wide comparisons. At a false discovery rate (FDR) of 5%, we had identified 28 such ID protein-encoding genes. Here, we assessed whether coding variants at these 28 genes affect QT interval in the general population as well. We used exome sequencing in 4,469 European American (EA) and 1,880 African American (AA) ancestry individuals from the population-based ARIC (Atherosclerosis Risk In Communities) Study cohort to focus on rare (allele frequency <1%) potentially deleterious (nonsynonymous, stop-gain, splice) variants (n = 2,398 for EA; n = 1,693 for AA) and tested their effects on standardized QT interval residuals. We identified 27 nonsynonymous variants associated with QT interval (FDR 5%), 22 of which were in TTN. Taken together with the mapping of a QT interval GWAS locus near TTN, our observation of rare deleterious coding variants in TTN associated with QT interval show that TTN plays a role in regulation of cardiac electrical conductance and coupling, and is a risk factor for cardiac arrhythmias and sudden cardiac death.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
Ashish
A
Kapoor
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
Kiranmayee
K
Bakshy
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
Linda
L
Xu
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
Priyanka
P
Nandakumar
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
Dongwon
D
Lee
Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center, Houston, Texas, 77030, USA.
Eric
E
Boerwinkle
Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center, Houston, Texas, 77030, USA.
Megan L
ML
Grove
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
Dan E
DE
Arking
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
Aravinda
A
Chakravarti
D001741:Black or African American; D000483:Alleles; D001145:Arrhythmias, Cardiac / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics*; D044383:Black People; D002874:Chromosome Mapping; D064211:Connectin / Q000235:genetics*; D016757:Death, Sudden, Cardiac; D004553:Electric Conductivity; D004562:Electrocardiography; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000166:cytology*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014481:United States; D044465:White People
D064211:Connectin; C577285:TTN protein, human