Transcriptome-wide association study identifies multiple genes and pathways associated with thyroid function
Transcriptome-wide association study identifies multiple genes and pathways associated with thyroid function
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DOI：
10.1093/hmg/ddab371
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Yan Guo
中科院分区：
文献类型：
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作者：
Xin Ke;Xin Tian;Shi Yao;Hao Wu;Yuan-Yuan Duan;Nai-Ning Wang;Wei Shi;Tie-Lin Yang;Shan-Shan Dong;Dageng Huang;Yan Guo
Abstract. Thyroid dysfunction is a common endocrine disease measured by thyroid-stimulating hormone (TSH) level. Although >70 genetic loci associated with TSH have been reported through genome-wide association studies (GWASs), the variants can only explain a small fraction of the thyroid function heritability. To identify novel candidate genes for thyroid function, we conducted the first large-scale transcriptome-wide association study (TWAS) for thyroid function using GWAS-summary data for TSH levels in up to 119 715 individuals combined with precomputed gene expression weights of six panels from four tissue types. The candidate genes identified by TWAS were further validated by TWAS replication and gene expression profiles. We identified 74 conditionally independent genes significantly associated with thyroid function, such as PDE8B (P = 1.67 × 10−282), PDE10A (P = 7.61 × 10−119), NR3C2 (P = 1.50 × 10−92) and CAPZB (P = 3.13 × 10−79). After TWAS replication using UKBB datasets, 26 genes were replicated for significant associations with thyroid-relevant diseases/traits. Among them, 16 genes were causal for their associations to thyroid-relevant diseases/traits and further validated in differential expression analyses, including two novel genes (MFSD6 and RBM47) that did not implicate in previous GWASs. Enrichment analyses detected several pathways associated with thyroid function, such as the cAMP signaling pathway (P = 7.27 × 10−4), hemostasis (P = 3.74 × 10−4), and platelet activation, signaling and aggregation (P = 9.98 × 10−4). Our study identified multiple candidate genes and pathways associated with thyroid function, providing novel clues for revealing the genetic mechanisms of thyroid function and disease.
