Effects of Thyroid Status on Regional Brain Volumes: A Diagnostic and Genetic Imaging Study in UK Biobank

Background: Thyroid hormone is essential for optimal human neurodevelopment and may modify the risk of attention-deficit/hyperactivity disorder (ADHD). However, the brain structures involved are unknown and it is unclear if the adult brain is also susceptible to changes in thyroid status. Methods: We used International Classification of Disease-10 codes, polygenic thyroid scores at different thresholds of association with thyroid traits (P-T-values), and image-derived phenotypes in UK Biobank (n = 18 825) to investigate the effects of a recorded diagnosis of thyroid disease and genetic risk for thyroid status on cerebellar and subcortical gray matter volume. Regional genetic pleiotropy between thyroid status and ADHD was explored using the GWAS-pairwise method. Results: A recorded diagnosis of hypothyroidism (n = 419) was associated with significant reductions in total cerebellar and pallidum gray matter volumes (beta [95% CI] = -0.14[-0.23, -0.06], P = 0.0005 and beta [95%CI] = -0.12 [-0.20, -0.04], P = 0.0042, respectively), mediated in part by increases in body mass index. While we found no evidence for total cerebellar volume alterations with increased polygenic scores for any thyroid trait, opposing influences of increased polygenic scores for hypo- and hyperthyroidism were found in the pallidum (P-T < 1e-3: beta [95% CI] = -0.02 [-0.03, -0.01], P = 0.0003 and P-T < 1e-7: beta [95% CI] = 0.02 [0.01, 0.03], P = 0.0003, respectively). Neither hypo- nor hyperthyroidism showed evidence of regional genetic pleiotropy with ADHD. Conclusions: Thyroid status affects gray matter volume in adults, particularly at the level of the cerebellum and pallidum, with potential implications for the regulation of motor, cognitive, and affective function.

Automated summary

The study found that a history of hypothyroidism was associated with significant reductions in cerebellar and pallidum gray matter volumes, partly mediated by increases in body mass index. It was also observed that polygenic scores for hypo- and hyperthyroidism had opposing influences on gray matter volumes, with no evidence of regional genetic pleiotropy with ADHD for either hypo- or hyperthyroidism.