Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

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Elderly persons with low-normal TSH levels have more concurrent depressive symptoms as well as a substantially increased risk of developing a depressive syndrome in the subsequent years. This study identifies low-normal TSH as an important risk factor for depression in the elderly.

Context Thyroid hormones (TH) are essential for brain development and function. The TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporter1 C1 (OATP1C1) facilitate the transport of TH across the blood-brain-barrier and into glia and neuronal cells in the brain. Loss of MCT8 function causes Allan-Herndon-Dudley syndrome (AHDS, OMIM 300523) characterized by severe intellectual and motor disability due to cerebral hypothyroidism. We describe the first patient with loss of OATP1C1 function. The patient was a 15.5-year-old girl with normal development in the first year of life, who gradually developed dementia with spasticity and intolerance to cold. Brain imaging demonstrated grey and white matter degeneration and severe glucose hypometabolism. Methods We performed exome sequencing of the patient and parents to identify the disease-causing mutation and studied the effect of the mutation through a panel of in vitro experiments, including T4 uptake studies, immunoblotting, and immunocytochemistry. Furthermore, we describe the clinical effects of treatment with the T3 analogue triiodothyroacetic acid (Triac). Results Exome sequencing identified a homozygous missense mutation in OATP1C1 changing the highly conserved Asp252 to an Asn. In vitro, the mutated OATP1C1 showed impaired plasma membrane localization and decreased cellular T4 uptake. After treatment with Triac the clinical condition improved in several domains. Conclusions This is the first report of human OATP1C1 deficiency, compatible with brain-specific hypothyroidism and neurodegeneration. Précis We describe a novel disease associated with mutated OATP1C1, a brain-specific thyroxine transporter expressed in astrocytes, characterized by brain hypometabolism and early-onset neurodegeneration.

We demonstrated that physiological levels of TH regulate a myriad of genes in human skeletal muscle. The identification of novel putatively TH-responsive genes may provide the molecular basis of clinical effects in subjects with different TH status. The observation that TH regulates microRNAs reveals a new layer of complexity by which TH influences cellular processes.