Introduction: There has been a substantial increase in our knowledge of the genetic architecture of thyroid function, with numerous variants associated with TSH and/or FT4 levels. However, our knowledge of the genetic variants associated with thyroid disease is more limited.
Methods: Data was obtained from the Neale laboratory† which provided a case-control study to identify single nucleotide polymorphisms associated with a diagnosis of hypothyroidism or hyperthyroidism. From this data there were 337,159 participants in UK Biobank, 16,376 with a diagnosis of hypothyroidism and 2,547 witha diagnosis of hyperthyroidism.
Results: We note 79 independent variants associated with hypothyroidism, several of which were novel. Novel genome-wide significance associations (P<5×10−08) were seen in variants in or near: C12ORF42, EDARADD, ELMO1, HIPK1, LINC00271, MIR1208, MIR6711, MIR7-3, MIR8071, NR1P1, PDE4A, PDX1, PLGRKT, PPP4R3B, RAD51B, SGK223, and SLC1A2. A novel variant in NRIP1 (a thyroid hormone repressor) appears to be an expression quantitative trait locus. Genome-wide levels of association were also seen for the first time in variants previously implicated in thyroid disease including TLR3, STAT1, TBX21, AAK1, RASGRP1, MIR3188 and LPP. Variants in PDE8B, CAPZB and FOXE-1, previously associated with TSH, were also associated with hypothyroidism. We also note 4 independent variants near PTPN22, CTLA4, TSHR and HLADQB1 at genome-wide levels of significance for hyperthyroidism; all were demonstrated in previous studies.
Conclusion: The substantial polygenic nature of the associations seen in multiple potential pathways with thyroid disease may explain its high prevalence. This work has also identified potential pathogenic pathways in genes associated with thyroid cancer and identified novel insights into thyroid disease. Intriguingly, few of the genetic variants associated with altered TSH and FT4 levels in the normal population were strongly associated with developing overt thyroid disease. †(http://www.nealelab.is/blog/2017/7/19/rapid-gwas-of-thousands-of-phenotypes-for-337000-samples-in-the-uk-biobank)