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Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians

Julie Guibon 1, 2, 3, 4 Pierre-Emmanuel Sugier 1, 2, 3 Om Kulkarni 2, 5 Mojgan Karimi 2, 1, 3 Delphine Bacq-Daian 2, 5 Céline Besse 2, 5 Anne Boland 2, 5 Elisabeth Adjadj 1, 2, 3 Frédérique Rachédi 6 Carole Rubino 2, 1, 3 Constance Xhaard 7, 8, 9, 10, 2, 1, 3 Claire Mulot 11, 12, 13 Pierre Laurent- Puig 11, 12, 13 Anne-Valérie Guizard 14, 15 Claire Schvartz 16 Rosa Ortiz 17 Yan Ren 2, 1, 3 Evgenia Ostroumova 18 Jean-François Deleuze 2, 5 Marie-Christine Boutron-Ruault 2, 1, 3 Ausrele Kesminiene 18 Florent de Vathaire 2, 1, 3 Pascal Guénel 2, 1, 3 Fabienne Lesueur 4 Thérèse Truong 2, 1, 3
Abstract : Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality. At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue. Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.
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Submitted on : Thursday, October 14, 2021 - 3:13:08 PM
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Julie Guibon, Pierre-Emmanuel Sugier, Om Kulkarni, Mojgan Karimi, Delphine Bacq-Daian, et al.. Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians. Oncotarget, Impact journals, 2021, 12 (5), pp.493-506. ⟨10.18632/oncotarget.27888⟩. ⟨hal-03378212⟩

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