Abstract P357: Genome-Wide Association Study of the PR Interval in Hispanic Populations

BACKGROUND: The PR interval (PR) is an electrocardiographic measure of atrial and atrioventricular nodal conduction. PR prolongation has been associated with atrial fibrillation, pacemaker implantation, heart failure, and all-cause mortality. Although Hispanic/Latino (HL) populations have high burdens of cardiovascular morbidity and mortality, they remain a chronically understudied population, with previous genome-wide association studies of PR limited to European (EU), African (AA), and Asian (AS) descent populations. METHODS: We included 13,507 participants of HL ancestry from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and Women’s Health Initiative clinical trials (WHI). PR was automatically measured from digital electrocardiogram tracings recorded using standardized methods in all participants. Genotype data were imputed to the 1000 Genomes Phase 1 reference panel, and associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry, study center or region, clinical covariates (age, sex, heart rate, height, body mass index, systolic blood pressure, beta blocker use), and study weights (HCHS/SOL only). Study-specific results were combined using a fixed-effects, inverse variance weighted meta-analysis. Linkage disequilibrium (LD) patterns were examined using LocusZoom, and r2 values were calculated using 1000 Genomes reference populations. RESULTS: We identified six loci associated with PR in HL populations at genome-wide significant levels: SLC8A1, SCN5A, SCN10A, ARHGAP24, CAV1/CAV2, and SOX5. At these loci, index SNPs had important effects (β range: 2-4 ms) and common minor allele frequencies (MAF range: 13-40%). Of note, five of the six identified loci were previously associated with PR in EU populations, and four in AA populations; however, the association with SLC8A1 has been found only in AS populations. Whereas the SLC8A1 index SNP, rs17026148, is common in AS (MAF = 50%), AA (MAF = 15%), and HL populations (MAF = 17%), it is rare in EU populations (MAF < 5%). Interestingly, SLC8A1 LD patterns are similar across AS, EU, and HL populations in this region. CONCLUSIONS: Our results suggest that genetic determinants of PR are consistent across race/ethnicity but that previous studies in EU populations were either underpowered to detect the SLC8A1 locus or that it resides on an Asian/American Indian haplotype, thus underscoring the importance of conducting genetic studies in diverse populations.

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An Academic Clinician’s Road Map to Hypertension Genomics

Hypertension ◽

10.1161/hypertensionaha.120.14535 ◽

2021 ◽

Author(s):

Emma F. Magavern ◽

Helen R. Warren ◽

Fu L. Ng ◽

Claudia P. Cabrera ◽

Patricia B. Munroe ◽

...

Keyword(s):

Big Data ◽

Essential Hypertension ◽

Clinical Benefit ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Road Map ◽

Genome Wide ◽

Cardiovascular Morbidity And Mortality

At the dawn of the new decade, it is judicious to reflect on the boom of knowledge about polygenic risk for essential hypertension supplied by the wealth of genome-wide association studies. Hypertension continues to account for significant cardiovascular morbidity and mortality, with increasing prevalence anticipated. Here, we overview recent advances in the use of big data to understand polygenic hypertension, as well as opportunities for future innovation to translate this windfall of knowledge into clinical benefit.

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Genome-Wide Association Studies of the PR Interval in African Americans

PLoS Genetics ◽

10.1371/journal.pgen.1001304 ◽

2011 ◽

Vol 7 (2) ◽

pp. e1001304 ◽

Cited By ~ 78

Author(s):

J. Gustav Smith ◽

Jared W. Magnani ◽

Cameron Palmer ◽

Yan A. Meng ◽

Elsayed Z. Soliman ◽

...

Keyword(s):

African Americans ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Pr Interval

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A Case Study of Fixed-Effects and Random-Effects Meta-Analysis Models for Genome-Wide Association Studies in Celiac Disease

Human Heredity ◽

10.1159/000437323 ◽

2015 ◽

Vol 80 (2) ◽

pp. 51-61 ◽

Cited By ~ 1

Author(s):

Richard S. Ahn ◽

Chad Garner

Keyword(s):

Celiac Disease ◽

Random Effects ◽

Fixed Effects ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Analysis Models

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Genome-wide association study of PR interval in Hispanics/Latinos identifies novel locus at ID2

Heart ◽

10.1136/heartjnl-2017-312045 ◽

2017 ◽

Vol 104 (11) ◽

pp. 904-911 ◽

Cited By ~ 6

Author(s):

Amanda A Seyerle ◽

Henry J Lin ◽

Stephanie M Gogarten ◽

Adrienne Stilp ◽

Raul Méndez Giráldez ◽

...

Keyword(s):

Association Study ◽

Fixed Effects ◽

Genome Wide Association Study ◽

Genetic Model ◽

Phase 1 ◽

Genome Wide Association ◽

Regulatory Function ◽

Genome Wide ◽

Cardiovascular Morbidity And Mortality ◽

Pr Interval

ObjectivePR interval (PR) is a heritable electrocardiographic measure of atrial and atrioventricular nodal conduction. Changes in PR duration may be associated with atrial fibrillation, heart failure and all-cause mortality. Hispanic/Latino populations have high burdens of cardiovascular morbidity and mortality, are highly admixed and represent exceptional opportunities for novel locus identification. However, they remain chronically understudied. We present the first genome-wide association study (GWAS) of PR in 14 756 participants of Hispanic/Latino ancestry from three studies.MethodsStudy-specific summary results of the association between 1000 Genomes Phase 1 imputed single-nucleotide polymorphisms (SNPs) and PR assumed an additive genetic model and were adjusted for global ancestry, study centre/region and clinical covariates. Results were combined using fixed-effects, inverse variance weighted meta-analysis. Sequential conditional analyses were used to identify independent signals. Replication of novel loci was performed in populations of Asian, African and European descent. ENCODE and RoadMap data were used to annotate results.ResultsWe identified a novel genome-wide association (P<5×10−8) with PR at ID2 (rs6730558), which replicated in Asian and European populations (P<0.017). Additionally, we generalised 10 previously identified PR loci to Hispanics/Latinos. Bioinformatics annotation provided evidence for regulatory function in cardiac tissue. Further, for six loci that generalised, the Hispanic/Latino index SNP was genome-wide significant and identical to (or in high linkage disequilibrium with) the previously identified GWAS lead SNP.ConclusionsOur results suggest that genetic determinants of PR are consistent across race/ethnicity, but extending studies to admixed populations can identify novel associations, underscoring the importance of conducting genetic studies in diverse populations.

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Association mapping from sequencing reads using k-mers

eLife ◽

10.7554/elife.32920 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 32

Author(s):

Atif Rahman ◽

Ingileif Hallgrímsdóttir ◽

Michael Eisen ◽

Lior Pachter

Keyword(s):

Population Stratification ◽

Reference Genome ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Structural Variations ◽

1000 Genomes ◽

Alignment Free ◽

Genome Wide ◽

Local Assembly

Genome wide association studies (GWAS) rely on microarrays, or more recently mapping of sequencing reads, to genotype individuals. The reliance on prior sequencing of a reference genome limits the scope of association studies, and also precludes mapping associations outside of the reference. We present an alignment free method for association studies of categorical phenotypes based on counting k-mers in whole-genome sequencing reads, testing for associations directly between k-mers and the trait of interest, and local assembly of the statistically significant k-mers to identify sequence differences. An analysis of the 1000 genomes data show that sequences identified by our method largely agree with results obtained using the standard approach. However, unlike standard GWAS, our method identifies associations with structural variations and sites not present in the reference genome. We also demonstrate that population stratification can be inferred from k-mers. Finally, application to an E.coli dataset on ampicillin resistance validates the approach.

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