Rare coding TTN variants are associated with electrocardiographic QT interval in the general population.

Pubmed ID: 27321809

Pubmed Central ID: PMC4913250

Journal: Scientific reports

Publication Date: June 20, 2016

MeSH Terms: Humans, Male, Female, Risk Factors, United States, Alleles, Gene Frequency, Middle Aged, Polymorphism, Single Nucleotide, Genotype, Prospective Studies, Atherosclerosis, Electrocardiography, Death, Sudden, Cardiac, Sequence Analysis, DNA, Arrhythmias, Cardiac, Chromosome Mapping, Gene Deletion, Myocytes, Cardiac, Connectin, Electric Conductivity, Black People, White People, Black or African American

Grants: HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01 HL059367, R01 HL086694, R01 HL087641, RC2 HL102419, U54 HG003273, R01 GM104469, R01 HL128782, HHSN268201100009I, HHSN268201100005G, HHSN268201100008I, HHSN268201100011I, HHSN268201100005I, HHSN268201100007I, T32 GM007814

Authors: Arking DE, Lee D, Kapoor A, Boerwinkle E, Grove ML, Chakravarti A, Bakshy K, Xu L, Nandakumar P

Cite As: Kapoor A, Bakshy K, Xu L, Nandakumar P, Lee D, Boerwinkle E, Grove ML, Arking DE, Chakravarti A. Rare coding TTN variants are associated with electrocardiographic QT interval in the general population. Sci Rep 2016 Jun 20;6:28356.

Studies:

Abstract

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.