Genome-Wide Association Analysis and Genomic Prediction of Thyroglobulin Plasma Levels

Abstract

Thyroglobulin (Tg) is an iodoglycoprotein produced by thyroid follicular cells which acts as an essential substrate for thyroid hormone synthesis. To date, only one genome-wide association study (GWAS) of plasma Tg levels has been performed by our research group. Utilizing recent advancements in computation and modeling, we apply a Bayesian approach to the probabilistic inference of the genetic architecture of Tg. We fitted a Bayesian sparse linear mixed model (BSLMM) and a frequentist linear mixed model (LMM) of 7,289,083 variants in 1096 healthy European-ancestry participants of the Croatian Biobank. Meta-analysis with two independent cohorts (total n = 2109) identified 83 genome-wide significant single nucleotide polymorphisms (SNPs) within the ST6GAL1 gene (p<5×10−8). BSLMM revealed additional association signals on chromosomes 1, 8, 10, and 14. For ST6GAL1 and the newly uncovered genes, we provide physiological and pathophysiological explanations of how their expression could be associated with variations in plasma Tg levels. We found that the SNP-heritability of Tg is 17% and that 52% of this variation is due to a small number of 16 variants that have a major effect on Tg levels. Our results suggest that the genetic architecture of plasma Tg is not polygenic, but influenced by a few genes with major effects.

Role of ST6GAL1 in Thyroid Cancers: Insights from Tissue Analysis and Genomic Datasets

“…Genome-wide association studies (GWAS) commonly used to unravel the genetic basis of polygenic disorders were used in research on thyroid-cancer-specific germline variants [8][9][10][11][12][13][14][15][16][17][18]. Our recent GWAS identified that the gene encoding for ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) was associated with plasma thyroglobulin (Tg) levels [19] and the result was confirmed in the replication study of our research group after including over a thousand new individuals, emphasizing that ST6GAL1 significantly contributes to the variation of Tg plasma levels [20].…”

“…The strength of our current study is that we analyzed the ST6GAL1 protein expression in different types of well-differentiated thyroid cancers. We decided to conduct this study since our previous GWA studies showed that certain variants of the ST6GAL1 gene were associated with plasma Tg levels [19,20]. Tg is the most abundant protein in the thyroid gland that releases thyroid hormones by proteolysis [39] and has increased plasma levels in thyroid pathology [40].…”