Objective PR 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.
Methods Study-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.
Results We 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.
Conclusions Our 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.
- genome-wide association studies (GWAS)
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Contributors The following individuals were involved in the planning stages of the manuscript, including project development and analysis design: AAS, HJL, SMG, AS, RMG, ES, SH, KFK, CK, CR, NS, KDT, EAW, JIR, CCL and CA. The following individuals were involved in data collection and cleaning: HJL, ES, SH, CK, CR, XG, NS, EAW, JIR and CCL. The following individuals were involved in data analysis: AAS, SMG, AS, AB, MG, XG, JY and CCL. The following individuals were involved in manuscript preparation, editing and revision: AAS, HJL, AS, RMG, SH, KFK, NS, KDT, EAW, JIR, CCL and CA. Furthermore, all authors reviewed the final version of the manuscript and provided critiques.
Funding The following Institutes/Centers/Offices contributed to the first phase of HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, and NIH Institution–Office of Dietary Supplements. The Genetic Analysis Center at University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Genotyping efforts were supported by NHLBI HSN 26220/20054C, NCATS CTSI grant UL1TR000124 and NIDDK Diabetes Research Center (DRC) grant DK063491. AAS was also supported by training grants T32HL7055 and T32HL07779. NS was supported by R01HL116747 and R01 HL111089. Multi-Ethnic Study of Atherosclerosis (MESA): This research was supported by the Multi-Ethnic Study of Atherosclerosis (MESA) contracts HHSN2682015000031, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and by grants UL1-TR-000040, UL1-TR-001079 and UL1-RR-025005 from NCRR. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. We also thank the other investigators, the staff and the participants of MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found online (http://www.mesa-nhlbi.org).
Competing interests None declared.
Ethics approval North Carolina.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Complete summary level results from this analysis will be made available on dbGap.
Correction notice Since this paper was first published online the middle initial L has been added to the author name Christy Avery.