Genetic Thyrotropin Regulation of Atrial Fibrillation Risk Is Mediated Through an Effect on Height.

TLDR: In this article, the authors used two-sample Mendelian randomization (MR) to test associations between TSH-associated single nucleotide polymorphisms (SNPs) and 16 candidate mediators.

Abstract: Background A genetic predisposition to lower thyroid stimulating hormone (TSH) levels associates with increased atrial fibrillation (AF) risk through undefined mechanisms. Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk. Methods We used two-sample Mendelian randomization (MR) to test associations between TSH-associated single nucleotide polymorphisms (SNPs) and 16 candidate mediators. We then performed multivariable Mendelian randomization (MVMR) to test for a significant attenuation of the genetic association between TSH and AF, after adjusting for each mediator significantly associated with TSH. Results Four candidate mediators (free T4, systolic blood pressure, heart rate, and height) were significantly inversely associated with genetically predicted TSH after adjusting for multiple testing. In MVMR analyses, adjusting for height significantly decreased the magnitude of the association between TSH and AF from -0.12 (s.e. 0.02) occurrences of AF per standard deviation change in height to -0.06 (0.02) (p=0.005). Adjusting for the other candidate mediators did not significantly attenuate the association. Conclusions The genetic association between TSH and increased AF risk is mediated, in part, by taller stature. Thus, some genetic mechanisms underlying TSH variability may contribute to AF risk through mechanisms determining height occurring early in life that differ from those driven by thyroid hormone level elevations in later life.