Objectives

Recent GWAS in adults have identified 20 genetic variants associated with serum free thyroxine (FT4) concentrations that explained 4.8% of the variability in FT4. These include a variant in AADAT, which encodes a novel thyroid hormone metabolizing enzyme. We aimed to replicate and quantify the effects of these novel genetic variants in pregnant women, newborns and during childhood as thyroid hormone physiology in pregnancy and childhood differs from adulthood.

Methods

We selected participants from a population-based prospective cohort with data on maternal or child genetic variants and maternal gestational FT4 (N=3,000), cord blood FT4 (N=2,030), or childhood FT4 concentrations (N=1,410; median age 6y). Multivariable linear regression models were used to study the association of single nucleotide polymorphisms (SNPs) with maternal and child FT4. Additionally, weighted polygenic risk scores (PRSs) were constructed to assess the combined effects of these SNPs in mothers or children.

Results

In mothers, variants rs2235544 and rs11078333 at the DIO1 and NCOR1 locus were associated with maternal FT4 after correction for multiple testing. In children, these variants were associated with childhood FT4. The PRS of maternal SNPs explained 1.6% of FT4 during pregnancy, whereas child SNPs explained 5.4% of FT4 at 6 years. In addition, rs7860634 at the LHX3 locus was associated with maternal FT4 and rs11726248 at the AADAT locus was associated with childhood FT4. There was no association of SNPs with cord blood FT4.

Conclusion

In this study, we replicated two FT4 SNPs in both pregnancy and childhood, one SNP in children at 6 years of age, and one SNP in pregnant women. These findings provide new knowledge about thyroid hormone physiology during pregnancy and childhood and indicate that the amount of genetically determined variability in FT4 differs from adulthood. Understanding the genetics of gestational thyroid function can help elucidate causality of the association between thyroid hormones and adverse pregnancy and child developmental outcomes.