Mathieu Samuel, Briend Mewen, Abner Erik, Couture Christian, Li Zhonglin, Bossé Yohan, Thériault Sébastien, Esko Tõnu, Arsenault Benoit J, Mathieu Patrick
Genomic Medecine and Molecular Epidemiology Laboratory, Quebec Heart and Lung Institute, Laval University, Québec, QC, Canada.
Quebec Heart and Lung Institute, Laval University, Québec, QC, Canada.
iScience. 2022 Aug 20;25(9):104992. doi: 10.1016/j.isci.2022.104992. eCollection 2022 Sep 16.
We carried out a genome-wide association analysis including 51,194 cases of hypothyroidism and 443,383 controls. In total, 139 risk loci were associated to hypothyroidism with genes involved in lymphocyte function. Candidate genes associated with hypothyroidism were identified by using molecular quantitative trait loci, colocalization, and enhancer-promoter chromatin looping. Mendelian randomization (MR) identified 42 blood expressed genes and circulating proteins as candidate causal molecules in hypothyroidism. Drug-gene interaction analysis provided evidence that immune checkpoint and tyrosine kinase inhibitors used in cancer therapy increase the risk of hypothyroidism. Hence, integrative mapping and MR support that expression of genes and proteins enriched in lymphocyte function are associated with the risk of hypothyroidism and provide genetic evidence for drug-induced hypothyroidism and identify actionable potential drug targets.
我们开展了一项全基因组关联分析，纳入了51194例甲状腺功能减退症患者和443383名对照。总共139个风险位点与甲状腺功能减退症相关，涉及淋巴细胞功能的基因。通过使用分子数量性状位点、共定位和增强子-启动子染色质环化，确定了与甲状腺功能减退症相关的候选基因。孟德尔随机化（MR）确定了42个血液表达基因和循环蛋白作为甲状腺功能减退症的候选因果分子。药物-基因相互作用分析提供了证据，表明癌症治疗中使用的免疫检查点抑制剂和酪氨酸激酶抑制剂会增加甲状腺功能减退症的风险。因此，综合图谱分析和孟德尔随机化支持淋巴细胞功能丰富的基因和蛋白质表达与甲状腺功能减退症风险相关，并为药物性甲状腺功能减退症提供遗传证据，识别可采取行动的潜在药物靶点。
