Mingjian Shi1, Ali M Manouchehri2, Christian M Shaffer2, Nataraja Sarma Vaitinadin2, Jacklyn N Hellwege2, Joe-Elie Salem3, Lea K Davis2, Jill H Simmons4, Dan M Roden1,2,5, M Benjamin Shoemaker2, Jane F Ferguson2, Jonathan D Mosley1,2. 1. Department of Biomedical Informatics & Center for Precision Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. 2. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. 3. Département de Pharmacologie, APHP, Sorbonne Université, INSERM, UNICO-GRECO Cardio-oncology Program, F75013 Paris, France. 4. Division of Pediatric Endocrinology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. 5. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37212, USA.
Abstract
CONTEXT: A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms. OBJECTIVE: Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk. METHODS: We used 2-sample mendelian randomization (MR) to test associations between TSH-associated single-nucleotide variations 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 thyroxine, 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 (SE 0.02) occurrences of AF per SD change in height to -0.06 (0.02) (P = .005). Adjusting for the other candidate mediators did not significantly attenuate the association. CONCLUSION: 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.
CONTEXT: A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms. OBJECTIVE: Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk. METHODS: We used 2-sample mendelian randomization (MR) to test associations between TSH-associated single-nucleotide variations 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 thyroxine, 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 (SE 0.02) occurrences of AF per SD change in height to -0.06 (0.02) (P = .005). Adjusting for the other candidate mediators did not significantly attenuate the association. CONCLUSION: 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.
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