Identification of three novel genetic variations associated with electrocardiographic traits (QRS duration and PR interval) in East Asians

Hong, Kyung Won; Lim, Ji Eun; Kim, Jong W.ook; Tabara, Yasuharu; Ueshima, Hirotsugu; Miki, Tetsuro; Matsuda, Fumihiko; S.hin, Cho, Yoon; Kim, Yeonjung; Oh, Bermseok

doi:10.1093/hmg/ddu374

Cited by 37 publications

(37 citation statements)

References 34 publications

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“…More than forty variants at this locus had significant or near significant eQTLs for CAV1/CAV2 in European American left atrial samples (Table S8). The most significant variant in the combined ancestry analysis (rs3801995) was in moderate LD (CEU r 2 =0.56) with the most significant variants in previous GWAS of PR-interval; 10, 15–17 which are in perfect LD (rs3807989 and rs11773845, CEU r 2 =1) with each other. The most significant variant in Europeans (rs13242816) was not in LD (CEU r 2 =0.11) with previously identified variants at this locus.…”

Section: Resultsmentioning

confidence: 88%

Fifteen Genetic Loci Associated With the Electrocardiographic P Wave

Christophersen¹,

Magnani²,

Yin³

et al. 2017

Circ Cardiovasc Genet

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Background The P-wave on an electrocardiogram is a measure of atrial electrical function and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study (GWAS) results for P-wave duration and P-wave terminal force from twelve cohort studies. Methods and Results We included 44,456 individuals, of which 6,778 (16%) were of African ancestry. Genotyping, imputation, and GWAS were performed at each study site. Summary level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified six significant (P<5×10−8) novel loci, and replicated a prior association with SCN10A. We identified three loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR-interval, PR-segment, and P-wave duration. We identified six novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P-wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction. Conclusions We have identified six novel genetic loci associated with P-wave duration and six novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

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Section: Resultsmentioning

confidence: 88%

Fifteen Genetic Loci Associated With the Electrocardiographic P Wave

Christophersen¹,

Magnani²,

Yin³

et al. 2017

Circ Cardiovasc Genet

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“…Intriguingly, this suggests that enhancer contacts between this locus and nearby genes may be evolutionarily conserved, which might also explain why genetic variation in this region has been associated with human disease, including colorectal cancer and cardiac defects (Sotoodehnia et al, 2010, Dunlop et al, 2012, Ritchie et al, 2013, Hong et al, 2014). Collectively, these data provide a starting point to better understand the exact nature of the regulatory interactions at this locus, which could ultimately provide important insights into the pathogenesis of several human diseases.…”

Section: Discussionmentioning

confidence: 98%

In Vivo Characterization of Linc-p21 Reveals Functional cis -Regulatory DNA Elements

et al. 2016

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Summary The Linc-p21 locus, encoding a long non-coding RNA, plays an important role in p53 signalling, cell cycle regulation, and tumour suppression. However, despite extensive study, confusion exists regarding its mechanism of action: is activity driven by the transcript acting in trans, in cis, or by an underlying functional enhancer? Here, using a knockout mouse model and a massively parallel enhancer assay, we delineate the functional elements at this locus. We observe that even in tissues with no detectable Linc-p21 transcript, deletion of the locus significantly affects local gene expression, including of the cell cycle regulator Cdkn1a. To characterize this RNA-independent regulatory effect, we systematically interrogated the underlying DNA sequence for enhancer activity at nucleotide resolution, and confirmed the existence of multiple enhancer elements. Together, these data suggest that, in vivo, the cis-regulatory effects mediated by Linc-p21, in the presence or absence of transcription, are due to DNA enhancer elements.

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“…Specifically, recent genome-wide association studies have identified genetic variants that are associated with risk of sick sinus syndrome27 and parameters of AV cardiac conduction 28. Further, some reports have suggested ethnic differences in single-nucleotide polymorphisms associated with cardiac QRS duration and P-R interval 29. While we are not aware of demonstration of such differences specifically between South Asian and white European populations, it is possible that the presence of ethnic-specific variants contribute to the relative protection of South Asians from bradycardias.…”

Section: Discussionmentioning

confidence: 99%