Faculty Collaboration Database

The history and geographic distribution of a KCNQ1 atrial fibrillation risk allele. Nat Commun 2021 Nov 08;12(1):6442

Date

11/10/2021

Pubmed ID

34750360

Pubmed Central ID

PMC8575962

DOI

10.1038/s41467-021-26741-7

Scopus ID

2-s2.0-85118668606 (requires institutional sign-in at Scopus site)   6 Citations

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.

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 M

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Action Potentials
Alleles
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