Dataset Information

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

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.

SUBMITTER: Guibon J

PROVIDER: S-EPMC7939525 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Guibon Julie J Sugier Pierre-Emmanuel PE Kulkarni Om O Karimi Mojgan M Bacq-Daian Delphine D Besse Céline C Boland Anne A Adjadj Elisabeth E Rachédi Frédérique F Rubino Carole C Xhaard Constance C Mulot Claire C Laurent-Puig Pierre P Guizard Anne-Valérie AV Schvartz Claire C Ortiz Rosa Maria RM Ren Yan Y Ostroumova Evgenia E Deleuze Jean-François JF Boutron-Ruault Marie-Christine MC Kesminiene Ausrele A De Vathaire Florent F Guénel Pascal P Lesueur Fabienne F Truong Thérèse T

Oncotarget 20210302 5

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 cond ...[more]

PMID: 33747362

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Project description:Recent genome-wide association studies have identified 78 loci associated with Parkinson's disease susceptibility but the underlying mechanisms remain largely unclear. To identify likely causal variants for disease risk, we fine-mapped these Parkinson's-associated loci using four different fine-mapping methods. We then integrated multi-assay cell type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus single nucleotide polymorphism (SNPs) that disrupt LRRK2 and FCGR2A regulatory elements in microglia, an MBNL2 enhancer in oligodendrocytes, and a DYRK1A enhancer in neurons. This genome-wide functional fine-mapping investigation of Parkinson's disease substantially advances our understanding of the causal mechanisms underlying this complex disease while avoiding focus on spurious, non-causal mechanisms. Together, these results provide a robust, comprehensive list of the likely causal variants, genes and cell-types underlying Parkinson's disease risk as demonstrated by consistently greater enrichment of our fine-mapped SNPs relative to lead GWAS SNPs across independent functional impact annotations. In addition, our approach prioritized an average of 3/85 variants per locus as putatively causal, making downstream experimental studies both more tractable and more likely to yield disease-relevant, actionable results. Large-scale studies comparing individuals with Parkinson's disease to age-matched controls have identified many regions of the genome associated with the disease. However, there is widespread correlation between different parts of the genome, making it difficult to tell which genetic variants cause Parkinson's and which are simply co-inherited with causal variants. We therefore applied a suite of statistical models to identify the most likely causal genetic variants (i.e. fine-mapping). We then linked these genetic variants with epigenomic and gene expression signatures across a wide variety of tissues and cell types to identify how these variants cause disease. Therefore, this study provides a comprehensive and robust list of cellular and molecular mechanisms that may serve as targets in the development of more effective Parkinson's therapeutics.

Dataset Information

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

Publications

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

Similar Datasets

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