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Cited by 20Cardiac electrophysiology and arrhythmiasGenetic Associations and EpidemiologyForensic and Genetic Research

The history and geographic distribution of a KCNQ1 atrial fibrillation risk allele

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Hateley, Shannon, Lopez-Izquierdo, Angelica, Jou, Chuanchau J., Cho, Scott, Schraiber, Joshua G., Song, Shiya, Maguire, Colin T., Torres, Natalia +26 more·2021·Nature Communications
DOI 10.1038/s41467-021-26741-7PMC PMC8575962
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Abstract

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins.

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  • There is a strong association between AF and genes KCNA5, SCN5A, and TTN, while LMNA and KCNQ1 present a weaker association with AF.

    “There is a strong association between AF and genes such as KCNA5, SCN5A and TTN, while genes like LMNA and KCNQ1 present a weaker association with AF [35,36,37,38].”

    From Atrial Fibrillation in Elite Athletes: A Comprehensive Review of the Literature (2024) · cites this paper as [37]

    The Introduction describes KCNQ1 R231H as a high-impact AF susceptibility allele, and the Discussion reports relatively high penetrance—79% by adulthood—in the studied family. That runs contrary to the claim’s characterization of KCNQ1 as weakly associated with AF. The paper does not compare KCNQ1’s association with the other genes named in the citing sentence. (LLM, conf=0.80)

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References 42 · Cited by 20

Research works printed but not linked: 38

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Authors
Hateley, S., Lopez-Izquierdo, A., Jou, C. J., Cho, S., Schraiber, J. G., Song, S., Maguire, C. T., Torres, N., Riedel, M., Bowles, N. E., Arrington, C. B., Kennedy, B. J., Etheridge, S. P., Lai, S., Pribble, C., Meyers, L., Lundahl, D., Byrnes, J., Granka, J. M., Kauffman, C. A., Lemmon, G., Boyden, S., Scott Watkins, W., Karren, M. A., Knight, S., Brent Muhlestein, J., Carlquist, J. F., Anderson, J. L., Chahine, K. G., Shah, K. U., Ball, C. A., Benjamin, I. J., Yandell, M., & Tristani-Firouzi, M.
Affiliations
  • University of Utah (US)
  • Medical College of Wisconsin (US)
  • Intermountain Medical Center (US)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-11-08
Volume
12
Issue
1
Pages
6442-6442
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-26741-7
PMC
PMC8575962
OpenAlex
W3214322918
Cited by
20
References
42
Citations by year
2026: 4 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 1
FWCI
2.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Nora Eccles Treadwell Foundation Utah Genome Project
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
Keywords
atrial fibrillation, KCNQ1, human migration history, population ancestry, iPSC-derived cardiomyocytes, action potential duration, Utah population
MeSH terms
Action Potentials, Alleles, Atrial Fibrillation, Denmark, Female, Genotype, Geography, Humans, Male, Middle Aged, Pedigree, Risk Factors, Utah, Genetic Predisposition to Disease, Mutation, Missense, Polymorphism, Single Nucleotide, Myocytes, Cardiac, KCNQ1 Potassium Channel, Emigrants and Immigrants, Induced Pluripotent Stem Cells

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