Genome-wide association meta-analysis for total thyroid hormone levels in Croatian population

Thyroid hormones (THs) are key regulators of cellular growth, development, and metabolism. The thyroid gland secretes two THs, thyroxine (T4) and triiodothyronine (T3), into the plasma where they are almost all bound reversibly to plasma proteins. Free forms of THs are metabolically active, however, they represent a very small fraction of total TH levels. No genome-wide studies have been performed to date on total TH levels, comprising of protein-bound and free forms of THs. To detect genetic variants associated with total TH levels, we carried out the first GWAS meta-analysis of total T4 levels in 1121 individuals from two Croatian cohorts (Split and Korcula). We also performed GWAS analyses of total T3 levels in 577 individuals and T3/T4 ratio in 571 individuals from the Split cohort. The top association in GWAS meta-analysis of total T4 was detected for an intronic variant within SLC22A9 gene (rs12282281, P = 4.00 × 10^-7). Within the same region, a genome-wide significant variant (rs11822642, P = 2.50 × 10^-8) for the T3/T4 ratio was identified. SLC22A9 encodes for an organic anion transporter protein expressed predominantly in the liver and belongs to the superfamily of solute carriers (SLC), a large group of transport membrane proteins. The transport of THs across the plasma membrane in peripheral tissues is facilitated by the membrane proteins, and all TH transport proteins known to date belong to the same SLC superfamily as SLC22A9. These results suggest a potential role for SLC22A9 as a novel transporter protein of THs.