Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease susceptibility and age-of-onset

Abstract

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Electronic health records were used to undertake the largest genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identified 158 novel signals, more than doubling the number of known associations with TSH, and implicating 112 putative causal genes, of which 78 were not previously implicated. For the first time, we demonstrate that a polygenic score for TSH was associated with TSH levels in all ancestries in UK Biobank, and strongly predicted age of onset of hypothyroidism and hyperthyroidism in European ancestry participants. We developed pathway-specific genetic risk scores for TSH levels and used these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum

“…We observed no genome-wide genetic correlations between any category of female infertility and: (i) any reproductive hormone in this study, or (ii) thyroid stimulating hormone (TSH), or (iii) anti-Mullerian hormone (AMH), the latter two based on publicly available summary statistics 74,75 (all P>0.05, Figure 3B). Mendelian randomisation (MR) analyses indicated a genetically causal protective effect of FSH on risk of F-ALL (OR (95% CI)=0.776 (0.678-0.888), P=2.15E-04) and F-EXCL (0.716 (0.604-0.850), P=1.26E-04) (Supp.…”

“…We estimated genetic correlations among the three categories of female infertility with significant heritability ( Z >4) 51 : F-ALL, F-ANOV, and F-INCL, as well as among heritable female reproductive hormones (FSH and testosterone in females). We additionally obtained summary statistics from GWASs of thyroid stimulating hormone (TSH) 75 (sex-combined analysis, N=247,107 participants) and anti-Mullerian hormone (N=7,049 pre-menopausal participants) 74 from the largest publicly available European-ancestry studies to date. We also tested for genetic correlations between infertility and reproductive hormones.…”

Genome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies

“…Consistency between the two hospitals involved examining the consistency of the effect direction of the lead SNPs and assessing the significance of the GWAS P-values in the Baoan and Longgang Studies. On the other hand, consistency of our meta-GWAS results and external datasets involved examining the consistency in an independent dataset from three separate cohorts (ThyroidOmics Consortium, the GWAS meta-analysis of Alexander T Williams et al, the GWAS meta-analysis of M. Medici et al) [10,11,34] . Beyond the participants previously referenced, our research included 4,688 individuals who attended Baoan District Maternal and Child Health Hospital for maternity check-ups during their 40-week gestation.…”

“…Twin and family studies estimate heritable contributions to approximately 64%-70.8% for serum TSH, 39%-80% for FT4 [7][8][9] , and 48.8% for anti-thyroid peroxidase antibody (TPOAb) [9] . Large-scale meta-genome-wide association studies of thyroid hormones among general European populations have identified lead SNPs explaining 22.8% of TSH variation and 4% of FT4 variation, respectively [10,11] . These studies suggest that genetics may also influence thyroid function measurements during gestation, an aspect that has been under-studied.…”