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

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. 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. 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. 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. This study only used GWAS data from individuals of European descent, so the findings may not apply to other ethnic groups.