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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Salem reported grants from Fondation Recherche Medicale (SPE20170336816) during the conduct of the study. Dr Shoemaker reported a grant from the National Institutes of Health (grant K23HL127704)Dr Larson reported grants from National Institutes of Health/National Human Genome Research Institute during the conduct of the study. Dr Davis reported grants from Vanderbilt University Medical Center during the conduct of the study. Dr Ellinor reported grants from Bayer AG to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation, personal fees from Novartis, and personal fees from Quest Diagnostics outside the submitted work. Dr Denny reported grants from National Institutes of Health during the conduct of the study. No other disclosures were reported.

Figures

Figure.. Association of AF Risk With Thyrotropin Levels

A, Scatterplot summarizing associations between the thyrotropin predictor and 11 diagnoses in 37 154 individuals in the BioVU eMERGE (Electronic Medical Records and Genetics) cohort. Each dot represents a disease association. Significant (P ≤ 1.89 × 10−5) associations are shown in orange, and selected diagnoses are labeled. B, Scatterplot comparing the associations with thyrotropin levels and atrial fibrillation (AF) risk for 24 single-nucleotide variants (SNVs) significantly associated with thyrotropin by prior genome-wide association studies in 17 931 individuals with AF and 115 142 controls in the AF Genetics cohort. The x-axis is the SD change in thyrotropin levels per copy of the reference allele and the y-axis is the change in the log(odds-ratio) of AF risk. The horizontal and vertical whiskers around each point represent the 95% CI for the thyrotropin and AF effect sizes, respectively. The line displays the results of an inverse-variance weighted average meta-analysis summarizing the association between thyrotropin levels and AF risk. NOS indicates not otherwise specified.