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Original Investigation
January 23, 2019

Association of Thyroid Function Genetic Predictors With Atrial Fibrillation: A Phenome-Wide Association Study and Inverse-Variance Weighted Average Meta-analysis

Author Affiliations
  • 1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 2Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM) CIC Paris-Est, AP-HP, Institute of Cardio metabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France
  • 3Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee
  • 4Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee
  • 5Department of Medicine (Medical Genetics), University of Washington, Seattle
  • 6Department Genome Sciences, University of Washington, Seattle
  • 7Kaiser Permanente Washington Health Research Institute, Seattle
  • 8Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee
  • 9Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee
  • 10Divisions of Human Genetics and Pulmonary Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 11Department of Biomedical Informatics, Columbia University, New York
  • 12Cardiovascular Research Center, Massachusetts General Hospital, Boston
  • 13The Broad Institute of Harvard and MIT, Cambridge, Massachusetts
JAMA Cardiol. 2019;4(2):136-143. doi:10.1001/jamacardio.2018.4615
Key Points

Question  Is there any association between a polygenic predictor of thyroid function and atrial fibrillation (AF) risk?

Findings  This phenome-wide association study of 37 154 individuals applied a genetic predictor of thyrotropin levels to an electronic health record cohort and identified expected associations with thyroid disorders as well as a significant inverse association with AF, even after dropping cases of overt thyroid disease. This finding was replicated in an AF genome-wide association study (17 931 AF cases and 115 142 controls).

Meaning  This study suggests a potential role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for this increasingly common arrhythmia.


Importance  Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF).

Objective  To determine the association between genetically determined thyrotropin levels and AF.

Design, Setting, and Participants  This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018.

Main Outcomes and Measures  Clinical diagnoses associated with a polygenic predictor of thyrotropin levels.

Exposures  Genetically determined thyrotropin levels.

Results  Of 37 154 individuals, 19 330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10−11) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10−8 for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10−7). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10−6). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17 931 AF cases and 115 142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10−4). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P = .04).

Conclusions and Relevance  This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.