Subtype-specific causal effects of hypothyroidism on obstructive sleep apnea: A bidirectional Mendelian randomization study

Abstract

This study investigates the subtype-specific causal relationships between hypothyroidism (HT) and obstructive sleep apnea (OSA) using a bidirectional Mendelian randomization (MR) design. A two-sample MR analysis was conducted based on genome-wide association study summary statistics from European populations, including multiple HT subtypes and thyroid function indicators. The inverse variance weighted method was used as the primary analysis, supplemented by MR-Egger regression, weighted median, and leave-one-out analyses. Sensitivity analyses assessed pleiotropy and heterogeneity. Bidirectional MR was performed to explore causal directions between HT and OSA. Hypothyroidism, drug reimbursement, hypothyroidism, strict autoimmune, and congenital iodine deficiency syndrome/HT were significantly associated with an increased risk of OSA. Thyroglobulin exhibited a protective causal effect against OSA. In the reverse MR analysis, genetically predicted OSA was found to causally increase the risk of hypothyroidism, drug reimbursement. No substantial pleiotropy was detected, and the findings were robust across multiple analytical methods. This study revealed subtype-specific and bidirectional causal associations between HT and OSA. The findings highlight the need for personalized screening and management strategies for patients with different forms of thyroid dysfunction.

Keywords: Mendelian randomization; causal inference; hypothyroidism; obstructive sleep apnea; subtype analysis; thyroglobulin.

Figure 1.

MR analysis results of hypothyroidism subtypes and thyroid function biomarkers associated with OSA. MR = Mendelian randomization.

Figure 2.

Mendelian randomization results for the causal association between specific hypothyroidism subtypes and OSA risk. (A–D) Causal relationship between HT-DR and OSA: Panel A shows the forest plot; Panel B shows the scatter plot; Panel C shows the funnel plot; Panel D shows the leave-one-out sensitivity analysis plot. (E–H) Causal relationship between HT-SA and OSA: Panel E shows the forest plot; Panel F shows the scatter plot; Panel G shows the funnel plot; Panel H shows the leave-one-out sensitivity analysis plot. (I–L) Causal relationship between CIDS and OSA: Panel I shows the forest plot; Panel J shows the scatter plot; Panel K shows the funnel plot; Panel L shows the leave-one-out sensitivity analysis plot. (M–P) Causal relationship between Tg and OSA: Panel M shows the forest plot; Panel N shows the scatter plot; Panel O shows the funnel plot; Panel P shows the leave-one-out sensitivity analysis plot. CIDS = congenital iodine deficiency syndrome/hypothyroidism, HT-DR: hypothyroidism, drug reimbursement, HT-SA = hypothyroidism, strict autoimmune, OSA = obstructive sleep apnea, Tg = thyroglobulin.

Figure 3.

Reverse MR analysis results of OSA with hypothyroidism subtypes and thyroid function biomarkers. OSA = obstructive sleep apnea.

Figure 4.

MR analysis of OSA and HT-DR. A shows the forest plot; B shows the scatter plot; Panel C shows the funnel plot; D shows the leave-one-out sensitivity analysis plot. HT-DR: hypothyroidism, drug reimbursement, OSA = obstructive sleep apnea.