Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts

Kathleen F Kerr; Christy L Avery; Henry J Lin; Laura M Raffield; Qian S Zhang; Brian L Browning; Sharon R Browning; Matthew P Conomos; Stephanie M Gogarten; Cathy C Laurie; Tamar Sofer; Timothy A Thornton; Chancellor Hohensee; Rebecca D Jackson; Charles Kooperberg; Yun Li; Raúl Méndez-Giráldez; Marco V Perez; Ulrike Peters; Alexander P Reiner; Zhu-Ming Zhang; Jie Yao; Nona Sotoodehnia; Kent D Taylor; Xiuqing Guo; Leslie A Lange; Elsayed Z Soliman; James G Wilson; Jerome I Rotter; Susan R Heckbert; Deepti Jain; Eric A Whitsel

doi:10.1016/j.hrthm.2017.06.018

Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts

Heart Rhythm. 2017 Nov;14(11):1675-1684. doi: 10.1016/j.hrthm.2017.06.018. Epub 2017 Jun 10.

Authors

Kathleen F Kerr¹, Christy L Avery², Henry J Lin³, Laura M Raffield⁴, Qian S Zhang⁵, Brian L Browning⁶, Sharon R Browning⁷, Matthew P Conomos⁷, Stephanie M Gogarten⁷, Cathy C Laurie⁷, Tamar Sofer⁷, Timothy A Thornton⁷, Chancellor Hohensee⁸, Rebecca D Jackson⁹, Charles Kooperberg⁸, Yun Li¹⁰, Raúl Méndez-Giráldez², Marco V Perez¹¹, Ulrike Peters⁸, Alexander P Reiner¹², Zhu-Ming Zhang¹³, Jie Yao³, Nona Sotoodehnia¹⁴, Kent D Taylor³, Xiuqing Guo³, Leslie A Lange⁴, Elsayed Z Soliman¹³, James G Wilson¹⁵, Jerome I Rotter³, Susan R Heckbert¹⁶, Deepti Jain⁷, Eric A Whitsel¹⁷

Affiliations

¹ Department of Biostatistics, University of Washington, Seattle, Washington. Electronic address: katiek@uw.edu.
² Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
³ The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California.
⁴ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁵ Department of Biostatistics, University of Washington, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.
⁶ Department of Medicine, University of Washington, Seattle, Washington.
⁷ Department of Biostatistics, University of Washington, Seattle, Washington.
⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
⁹ Division of Endocrinology, Diabetes and Metabolism, College of Medicine, The Ohio State University, Columbus, Ohio.
¹⁰ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
¹¹ Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Palo Alto, California.
¹² Department of Epidemiology, University of Washington, Seattle, Washington.
¹³ Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, North Carolina.
¹⁴ Department of Epidemiology, University of Washington, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
¹⁵ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
¹⁶ Department of Epidemiology, University of Washington, Seattle, Washington; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
¹⁷ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Abstract

Background: Although time-domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized.

Objective: The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767).

Methods: We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P <5 × 10^-8) or suggestive (P <10^-6) significance thresholds.

Results: Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms.

Conclusion: This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits.

Keywords: Autonomic nervous system; Electrocardiogram; Epidemiology; Genetic association studies; Ion channels/membrane transport.

Publication types

Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial

MeSH terms

Arrhythmias, Cardiac / ethnology
Arrhythmias, Cardiac / genetics*
Autonomic Nervous System / physiopathology*
Black or African American*
Electrocardiography
Genome-Wide Association Study / methods*
Genotype
Heart Rate / genetics*
Hispanic or Latino*
Humans
Phenotype
Polymorphism, Single Nucleotide*
United States / epidemiology

Abstract

Publication types

MeSH terms

Grants and funding