The history and geographic distribution of a KCNQ1 atrial fibrillation risk allele. Nat Commun 2021 Nov 08;12(1):6442
Date
11/10/2021Pubmed ID
34750360Pubmed Central ID
PMC8575962DOI
10.1038/s41467-021-26741-7Scopus ID
2-s2.0-85118668606 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
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.
Author List
Hateley S, Lopez-Izquierdo A, Jou CJ, Cho S, Schraiber JG, Song S, Maguire CT, Torres N, Riedel M, Bowles NE, Arrington CB, Kennedy BJ, Etheridge SP, Lai S, Pribble C, Meyers L, Lundahl D, Byrnes J, Granka JM, Kauffman CA, Lemmon G, Boyden S, Scott Watkins W, Karren MA, Knight S, Brent Muhlestein J, Carlquist JF, Anderson JL, Chahine KG, Shah KU, Ball CA, Benjamin IJ, Yandell M, Tristani-Firouzi MAuthor
Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Action PotentialsAlleles
Atrial Fibrillation
Denmark
Emigrants and Immigrants
Female
Genetic Predisposition to Disease
Genotype
Geography
Humans
Induced Pluripotent Stem Cells
KCNQ1 Potassium Channel
Male
Middle Aged
Mutation, Missense
Myocytes, Cardiac
Pedigree
Polymorphism, Single Nucleotide
Risk Factors
Utah