TY - JOUR T1 - Fine-mapping and initial characterization of QT interval loci in African Americans. JF - PLoS Genet Y1 - 2012 A1 - Avery, Christy L A1 - Sethupathy, Praveen A1 - Buyske, Steven A1 - He, Qianchuan A1 - Lin, Dan-Yu A1 - Arking, Dan E A1 - Carty, Cara L A1 - Duggan, David A1 - Fesinmeyer, Megan D A1 - Hindorff, Lucia A A1 - Jeff, Janina M A1 - Klein, Liviu A1 - Patton, Kristen K A1 - Peters, Ulrike A1 - Shohet, Ralph V A1 - Sotoodehnia, Nona A1 - Young, Alicia M A1 - Kooperberg, Charles A1 - Haiman, Christopher A A1 - Mohlke, Karen L A1 - Whitsel, Eric A A1 - North, Kari E KW - African Americans KW - Aged KW - Computational Biology KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors KW - Tachycardia KW - United States AB -

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

VL - 8 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22912591?dopt=Abstract ER - TY - JOUR T1 - Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval. JF - Epidemiology Y1 - 2014 A1 - Seyerle, Amanda A A1 - Young, Alicia M A1 - Jeff, Janina M A1 - Melton, Phillip E A1 - Jorgensen, Neal W A1 - Lin, Yi A1 - Carty, Cara L A1 - Deelman, Ewa A1 - Heckbert, Susan R A1 - Hindorff, Lucia A A1 - Jackson, Rebecca D A1 - Martin, Lisa W A1 - Okin, Peter M A1 - Perez, Marco V A1 - Psaty, Bruce M A1 - Soliman, Elsayed Z A1 - Whitsel, Eric A A1 - North, Kari E A1 - Laston, Sandra A1 - Kooperberg, Charles A1 - Avery, Christy L KW - Aged KW - Continental Population Groups KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors AB -

BACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.

METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.

RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.

CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

VL - 25 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25166880?dopt=Abstract ER - TY - JOUR T1 - 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. JF - Heart Rhythm Y1 - 2017 A1 - Avery, Christy L A1 - Wassel, Christina L A1 - Richard, Melissa A A1 - Highland, Heather M A1 - Bien, Stephanie A1 - Zubair, Niha A1 - Soliman, Elsayed Z A1 - Fornage, Myriam A1 - Bielinski, Suzette J A1 - Tao, Ran A1 - Seyerle, Amanda A A1 - Shah, Sanjiv J A1 - Lloyd-Jones, Donald M A1 - Buyske, Steven A1 - Rotter, Jerome I A1 - Post, Wendy S A1 - Rich, Stephen S A1 - Hindorff, Lucia A A1 - Jeff, Janina M A1 - Shohet, Ralph V A1 - Sotoodehnia, Nona A1 - Lin, Dan Yu A1 - Whitsel, Eric A A1 - Peters, Ulrike A1 - Haiman, Christopher A A1 - Crawford, Dana C A1 - Kooperberg, Charles A1 - North, Kari E AB -

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(-5)) 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.

VL - 14 IS - 4 ER -