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Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations.

Citation
Avery, C. L., et al. “Fine Mapping Of Qt Interval Regions In Global Populations Refines Previously Identified Qt Interval Loci And Identifies Signals Unique To African And Hispanic Descent Populations.”. Heart Rhythm, pp. 572-580.
Center UCSD-UCLA
Author Christy L Avery, Christina L Wassel, Melissa A Richard, Heather M Highland, Stephanie Bien, Niha Zubair, Elsayed Z Soliman, Myriam Fornage, Suzette J Bielinski, Ran Tao, Amanda A Seyerle, Sanjiv J Shah, Donald M Lloyd-Jones, Steven Buyske, Jerome I Rotter, Wendy S Post, Stephen S Rich, Lucia A Hindorff, Janina M Jeff, Ralph Shohet V, Nona Sotoodehnia, Dan Yu Lin, Eric A Whitsel, Ulrike Peters, Christopher A Haiman, Dana C Crawford, Charles Kooperberg, Kari E North
Keywords African American, electrocardiography, fine mapping, Hispanic/Latino, QT interval
Abstract

BACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance.

OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry.

METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis.

RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs.

CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.

Year of Publication
2017
Journal
Heart rhythm
Volume
14
Issue
4
Number of Pages
572-580
Date Published
12/2017
ISSN Number
1556-3871
DOI
10.1016/j.hrthm.2016.12.021
Alternate Journal
Heart Rhythm
PMID
27988371
PMCID
PMC5448160
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