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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. Many rare high-impact variants have been associated with disease, but the origins and functional impact are not always explored. Here, the authors trace the ancestry of a rare high impact atrial fibrillation allele in KCNQ1, and use iPSC-derived cardiomyocytes to characterize the effect of the allele. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex neurological trait. Allelic variation in the MHC class II region exerts the single strongest effect on MS genetic risk. The clinical onset of the disease is extremely variable, and can range from the first to the ninth decade of life. Epidemiological studies have suggested a modest genetic component to the age of onset (AO) of MS. Previous studies have shown that HLA-DRB1*1501 may be associated with a younger AO. Here, we sought to uncover any effect of HLA-DRB1*1501 on the AO of MS in a large Canadian cohort. A total of 1816 MS patients were genotyped for HLA-DRB1. Patients carrying HLA-DRB1*1501 were shown to have a small, but significantly lower, AO than patients without the allele (P=0.03). HLA-DRB1*1501 was also shown to reduce the mean AO in both progressive and relapsing forms of the disease. An investigation of parent-of-origin effects indicated that the lower AO for HLA-DRB1*1501 patients arises from maternally transmitted HLA-DRB1*1501 haplotypes (maternal HLA-DRB1*1501 mean AO=28.4 years, paternal=30.3 years; P=0.009). HLA-DRB1*1501 exerts a modest, but significant effect on the AO of all forms of MS. Parent-of-origin effects at the MHC are further implicated in MS disease pathogenesis. [ABSTRACT FROM AUTHOR]