Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: A genome-wide association study of 13,372 participants

Deo, Rajat; Nalls, Michael A.; Avery, Christy L.; Smith, J. G.; Evans, Daniel S.; Keller, Margaux F.; Butler, Anne M.; Buxbaum, Sarah G.; Li, G.; Quibrera, P. Miguel; Smith, Erin N.; Tanaka, Toshiko; Akylbekova, Ermeg L.; Alonso, Álvaro; Arking, Dan E.; Benjamin, Emelia J.; Berenson, Gerald S.; Bis, Joshua C.; Chen, L. Y.; Chen, W.; Cummings, Steven R.; Ellinor, Patrick T.; Evans, Michele K.; Ferrucci, Luigi; Fox, Ervin R.; Heckbert, Susan R.; Heiss, Gerardo; Hsueh, Wen-Chi; Kerr, Kathleen F.; Limacher, Marian C.; Liu, Y.; Lubitz, Steven A.; Magnani, Jared W.; Mehra, Reena; Marcus, Gregory M.; Murray, Sarah; Newman, Anne B.; Njajou, Omer T.; North, Kari E.; Paltoo, Dina N.; Psaty, Bruce M.; Redline, Susan; Reiner, Alex P.; Robinson, Jennifer G.; Rotter, Jerome I.; Samdarshi, Tandaw E.; Schnabel, Renate B.; Schork, Nicholas J.; Singleton, Andrew B.; Siscovick, David S.; Soliman, Elsayed Z.; Sotoodehnia, Nona; Srinivasan, Sathanur R.; Taylor, Herman A.; Trevisan, Maurizio; Zhang, Z.; Zonderman, Alan B.; Newton‐Cheh, Christopher; Whitsel, Eric A.

doi:10.1016/j.hrthm.2012.11.014

Cited by 29 publications

(19 citation statements)

References 34 publications

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“…This finding in mice is in agreement with a recent large genomewide association study in humans, where a genetic variant near the Cx43 gene is associated with variations in the resting heart rate [39], suggesting a role of Cx43 on the heart rate. Moreover conduction barriers to prevent the suppression of the pacemaker activity by the atrium, described as a sudden break of Cx43 expression, are important for the normal SAN function, and in humans with the SAN dysfunction, areas of nodal to atrial continuity have been detected [40].…”

Section: Bradycardia In Vegf 120/120 Embryos Due To Over-expression Osupporting

confidence: 92%

Abnormal sinoatrial node development resulting from disturbed vascular endothelial growth factor signaling

Calkoen

Vicente‐Steijn

Hahurij

et al. 2015

International Journal of Cardiology

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Section: Bradycardia In Vegf 120/120 Embryos Due To Over-expression Osupporting

confidence: 92%

Abnormal sinoatrial node development resulting from disturbed vascular endothelial growth factor signaling

Calkoen

Vicente‐Steijn

Hahurij

et al. 2015

International Journal of Cardiology

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“…Although a putative endophenotype for antisocial behavior and perhaps PTSD (see Table 5 ), resting heart rate has not received as much attention as an endophenotype as other candidates in Table 5 . Yet, as we discussed in section 6.1, GWAS meta-analyses of heart rate and related measures, such as Q-T interval, have identified several loci with genome-wide significant associations with heart rate in samples comprising subjects from different racial or ethnic backgrounds (European, Icelandic, Asian, African-American) (Cho et al, 2009; Deo et al, 2013; Eijgelsheim et al, 2010; Holm et al, 2010). There have been replicated findings, and several of the variants discovered are nonsynonymous and biologically plausible.…”

Section: 0 Selective Review Of Electrophysiological Biomarkers As Cmentioning

confidence: 99%

“…The effect sizes are small, accounting for no more than 1 beat per minute. For instance, one variant accounted for 0.4% of the variance in heart rate (shortening the R-R interval by 12.6 ms) (Deo et al, 2013). Other studies report somewhat smaller effects (see Figure 1 and Table 4 ).…”

Section: 0 Selective Review Of Electrophysiological Biomarkers As Cmentioning

confidence: 99%

Endophenotype best practices

Iacono

Malone

Vrieze

2017

International Journal of Psychophysiology

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This review examines the current state of electrophysiological endophenotype research and recommends best practices that are based on knowledge gleaned from the last decade of molecular genetic research with complex traits. Endophenotype research is being oversold for its potential to help discover psychopathology relevant genes using the types of small samples feasible for electrophysiological research. This is largely because the genetic architecture of endophenotypes appears to be very much like that of behavioral traits and disorders: they are complex, influenced by many variants (e.g., tens of thousands) within many genes, each contributing a very small effect. Out of over 40 electrophysiological endophenotypes covered by our review, only resting heart, a measure that has received scant advocacy as an endophenotype, emerges as an electrophysiological variable with verified associations with molecular genetic variants. To move the field forward, investigations designed to discover novel variants associated with endophenotypes will need extremely large samples best obtained by forming consortia and sharing data obtained from genome wide arrays. In addition, endophenotype research can benefit from successful molecular genetic studies of psychopathology by examining the degree to which these verified psychopathology-relevant variants are also associated with an endophenotype, and by using knowledge about the functional significance of these variants to generate new endophenotypes. Even without molecular genetic associations, endophenotypes still have value in studying the development of disorders in unaffected individuals at high genetic risk, constructing animal models, and gaining insight into neural mechanisms that are relevant to clinical disorder.

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“…Several gene candidates have been identifi ed across several GWAS (Deo et al, 2013;Eijgelsheim et al, 2010;Holm et al, 2010;Newton-Cheh et al, 2007). We highlight two genes with variants confi rmed for resting HR across populations that are of African, Asian, or European origins: (a) GJA1 that encodes connexin 43, the major protein constituent of the human myocardial gap junction, and (b) MYH6 (myosin, heavy chain 6, cardiac muscle, alpha) that encodes for a heavy chain subunit of cardiac muscle myosin (Deo et al, 2013).…”

Section: Heart Rate Variabilitymentioning

confidence: 99%

Etiology of Individual Differences in Human Health and Longevity

Finkel¹,

Gerritsen²,

Reynolds³

et al. 2014

annu rev gerontol geriatr

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In this chapter, we review of the fi eld of gerontological genetics with respect to subjective and objective health, the role of stress on health, and fi nally frailty and longevity. For most indices of subjective and objective health, frailty, and longevity, genetic infl uences contribute only modestly to individual differences, wherein heritabilities are typically on the order of 35%-40%. Notable exceptions are the moderate to strong heritabilities for lipid measures and brain structure and function, with a remarkably increasing role of genetic infl uences for longevity with advancing age. Although candidate gene and genome-wide association studies (GWAS) studies have identifi ed gene variants associated with many subjective and objective health traits, their effect sizes are typically relatively small, as expected for complex traits. There is some evidence for gene-environment interactions, and stress may be an important moderator of genetic variance for health. For example, carrying a risk genotype for cardiovascular disease (CVD) in the angiotensin converting enzyme gene ( ACE ) may predict stress responsivity and risk of cardiovascular-related diagnoses. Moreover, the gene coding for apolipoprotein E ( APOE ) may moderate responsiveness to stress evoking experiences, impact of physical exercise, and associate with sleep characteristics in those who develop cognitive impairments. For metabolic syndrome (MetS), encompassing the co-occurrence of obesity, hypertension, hypertriglyceridemia, 190 ANNUAL REVIEW OF GERONTOLOGY AND GERIATRICS and hyperinsulinemia, promising associations exist although no single genotype or any gene clusters have been consistently associated with MetS across populations, suggesting that complex gene-environment interactions must be understood before the use of genetic markers can be realized in clinical practice. Future investigations of subjective and objective health, frailty, and longevity are needed to further identify sources of genetic and environmental contributionsand their dynamics across adulthood-to advance understanding of aging processes, prevention, and intervention avenues, and ultimately successful aging.

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Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: A genome-wide association study of 13,372 participants

Cited by 29 publications

References 34 publications

Abnormal sinoatrial node development resulting from disturbed vascular endothelial growth factor signaling

Abnormal sinoatrial node development resulting from disturbed vascular endothelial growth factor signaling

Endophenotype best practices

Etiology of Individual Differences in Human Health and Longevity

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