Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

GWAS of Dizygotic Twinning in an Enlarged Australian Sample of Mothers of DZ Twins.

Female fertility is a complex trait with age-specific changes in spontaneous dizygotic (DZ) twinning and fertility. To elucidate factors regulating female fertility and infertility, we conducted a genome-wide association study (GWAS) on mothers of spontaneous DZ twins (MoDZT) versus controls (3273 cases, 24,009 controls). This is a follow-up study to the Australia/New Zealand (ANZ) component of that previously reported (Mbarek et al., 2016), with a sample size almost twice that of the entire discovery sample meta-analysed in the previous article (and five times the ANZ contribution to that), resulting from newly available additional genotyping and representing a significant increase in power. We compare analyses with and without male controls and show unequivocally that it is better to include male controls who have been screened for recent family history, than to use only female controls. Results from the SNP based GWAS identified four genomewide significant signals, including one novel region, ZFPM1 (Zinc Finger Protein, FOG Family Member 1), on chromosome 16. Previous signals near FSHB (Follicle Stimulating Hormone beta subunit) and SMAD3 (SMAD Family Member 3) were also replicated (Mbarek et al., 2016). We also ran the GWAS with a dominance model that identified a further locus ADRB2 on chr 5. These results have been contributed to the International Twinning Genetics Consortium for inclusion in the next GWAS meta-analysis (Mbarek et al., in press).

Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3.

OBJECTIVE: Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental vs genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance. METHODS: Heritability of thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.9-16.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these individuals across 7 522 526 SNPs as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study (n = 1115) followed by meta-analysis to maximise power for discovery. RESULTS: Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.7-74.9%) for TSH, 67.5% (59.8-75.3%) for fT4, 59.7% (54.4-65.0%) for fT3 and 48.8% (40.6-56.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3, and fT3 and rs12687280 near SERPINA7. Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4. CONCLUSION: Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.

Changes in Thyroid Function Across Adolescence: A Longitudinal Study.

OBJECTIVE: There are no large, longitudinal studies of thyroid function across adolescence. The aims of this study were to examine longitudinal trends in thyrotropin (TSH), free triiodothyronine (fT3) and free thyroxine (fT4) and determine age-specific reference ranges. METHODS: Thyroid function was assessed in 3415 participants in the Brisbane Longitudinal Twin Study at ages 12, 14, and 16, using the Abbott ARCHITECT immunoassay. Longitudinal analyses were adjusted for body mass index and puberty. RESULTS: In girls, mean fT4 (± SE) increased between age 12 and 14 (by 0.30 ±â€…0.08 pmol/L; P < 0.001), while remaining unchanged in boys; from age 14 to 16, fT4 increased in both girls (by 0.42 ±â€…0.07 pmol/L; P < 0.001) and boys (0.64 ±â€…0.07 pmol/L, P < 0.001). There was a slight increase in fT3 from age 12 to 14 years in girls (by 0.07 ±â€…0.03 pmol/L; P = 0.042), with a more marked increase in boys (0.29 ±â€…0.03 pmol/L; P < 0.001), followed by a decrease from age 14 to 16 in both sexes (girls, by 0.53 ±â€…0.02 pmol/L; P < 0.001; boys, by 0.62 ±â€…0.03 pmol/L; P < 0.001). From age 12 to 14, TSH showed no significant change in girls or boys, then levels increased from age 14 to 16 in both sexes (in girls, by 4.9%, 95% CI: 2.4%-10.3%, P = 0.020; in boys, by 7.2%, 95% CI: 3.0%-11.6%, P = 0.001). Reference ranges differed substantially from adults, particularly for fT4 and fT3. CONCLUSIONS: Thyroid function tests in adolescents display complex, sexually dimorphic patterns. Implementation of adolescence-specific reference ranges may be appropriate.