Evaluation of Circulating Proteins in Thyroid Cancer: Proteome-wide Mendelian Randomization and Colocalization Analyses

<b>Background: </b>Amidst a concerning upward trend in thyroid cancer (TC) cases worldwide. Investigating the shared genetic components between proteins and TC enhances our understanding of the disease's pathogenesis.<b>Methods:</b> We employed five large-scale multi-ethnic circulating proteomic genome-wide association studies (GWASs) with up to 100,000 participants and a TC Meta-GWAS (n_Case=3418, n_Control=292703) for bidirectional Mendelian Randomization (MR) and Bayesian colocalization analysis. Thyroid tissue-specific protein and gene expression were validated using data from our multi-omic cohort and public databases.<b>Results:</b> A total of 1525 proteins replicated in both discovery and replication cohorts were included. Through MR analysis, we identified 26 circulating proteins with a putative causal relationship with TCs, with NANS protein passing multiple corrections in both cohorts (<i>P</i>_BH=3.28e-5, 0.05/1525). These proteins were enriched in amino acids, carboxylic acids, sulfur-containing compounds metabolism, and organic acid synthesis pathways. Bayesian colocalization analysis further identified six proteins with moderate to strong evidence (PPH4 &gt; 0.5) of association with TCs (VCAM1, LGMN, NPTX1, PLEKHA7, TNFAIP3, and BMP1). Tissue-specific validation confirmed the differential expression of several identified proteins, notably BMP1, LGMN, and PLEKHA7, between normal and TC tissues.<b>Conclusions: </b>Our study indicates limited evidence for a link between circulating proteins and the risk of TCs. We have highlighted the contribution of circulating proteins, particularly those involved in amino acid metabolism pathways and genes, to TCs. This research has revealed several putative causal relationships between specific proteins and TC risk.