Thyroid function variations within the reference range and cognitive function: A two-sample Mendelian randomization study.

Background: The causal relationship between thyroid function variations within the reference range and cognitive function remains unknown. We aimed to explore this causal relationship using a Mendelian randomization (MR) approach.
Methods: Summary statistics of a thyroid function genome-wide association study (GWAS) were obtained from the ThyroidOmics consortium, including reference range thyroid stimulating hormone (TSH) (N = 54,288) and reference range free thyroxine (FT4) (N = 49,269). GWAS summary statistics on cognitive function were obtained from the Social Science Genetic Association Consortium (SSGAC) and the UK Biobank, including cognitive performance (N = 257,841), prospective memory (N = 152,605), reaction time (N = 459,523), and fluid intelligence (N = 149,051). The primary method used was inverse-variance weighted (IVW), supplemented with weighted median, Mr-Egger regression, and MR-Pleiotropy Residual Sum and Outlier. Several sensitivity analyses were conducted to identify heterogeneity and pleiotropy.
Results: An increase in genetically associated TSH within the reference range was suggestively associated with a decline in cognitive performance (β = -0.019; 95%CI: -0.034 to -0.003; P = 0.017) and significantly associated with longer reaction time (β = 0.016; 95 % CI: 0.005 to 0.027; P = 0.004). Genetically associated FT4 levels within the reference range had a significant negative relationship with reaction time (β = -0.030; 95%CI:-0.044 to -0.015; P = 4.85 × 10 ^-5 ). These findings remained robust in the sensitivity analyses.
Conclusions: Low thyroid function within the reference range may have a negative effect on cognitive function, but further research is needed to fully understand the nature of this relationship.
Limitations: This study only used GWAS data from individuals of European descent, so the findings may not apply to other ethnic groups.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
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