Reeve Mary, Kanai Masahiro, Graham Daniel, Karjalainen Juha, Luo Shuang, Kolosov Nikita, Adams Cameron, Ritari Jarmo, Karczewski Konrad, Kiiskinen Tuomo, Fuller Zachary, Mehtonen Juha, Kurki Mitja, Khan Zia, Partanen Jukka, McCarthy Mark, Artomov Mykyta, Tuomi Tiinamaija, Pirinen Matti, Kero Jukka, Xavier Ramnik, Daly Mark, Ripatti Samuli, Gen Finn
Institute for Molecular Medicine Finland (FiMM).
Broad Institute of MIT and Harvard.
Res Sq. 2024 Jul 8:rs.3.rs-4626646. doi: 10.21203/rs.3.rs-4626646/v1.
The high prevalence of autoimmune hypothyroidism (AIHT) - more than 5% in human populations - provides a unique opportunity to unlock the most complete picture to date of genetic loci that underlie systemic and organ-specific autoimmunity. Using a meta-analysis of 81,718 AIHT cases in FinnGen and the UK Biobank, we dissect associations along axes of thyroid dysfunction and autoimmunity. This largest-to-date scan of hypothyroidism identifies 418 independent associations (p < 5×10), more than half of which have not previously been documented in thyroid disease. In 48 of these, a protein-coding variant is the lead SNP or is highly correlated (r > 0.95) with the lead SNP at the locus, including low-frequency coding variants at as well as established variants at and . The variants at (P67T), (T155M), and (Q655X) are highly enriched in Finland and functional experiments in T-cells demonstrate that the :T155M allele reduces T-cell activation. By employing a large-scale scan of non-thyroid autoimmunity and a published meta-analysis of TSH levels, we use a Bayesian classifier to dissect the associated loci into distinct groupings and from this estimate, a significant proportion are involved in systemic (i.e., general to multiple autoimmune conditions) autoimmunity (34%) and another subset in thyroid-specific dysfunction (17%). By comparing these association results further to other common disease endpoints, we identify a noteworthy overlap with skin cancer, with 10% of AIHT loci showing a consistent but opposite pattern of association where alleles that increase the risk of hypothyroidism have protective effects for skin cancer. The association results, including genes encoding checkpoint inhibitors and other genes affecting protein levels of PD1, bolster the causal role of natural variation in autoimmunity influencing cancer outcomes.
自身免疫性甲状腺功能减退症（AIHT）在人群中的高患病率超过5%，为揭示迄今为止系统性和器官特异性自身免疫潜在的基因座全貌提供了独特契机。通过对芬兰基因库（FinnGen）和英国生物银行（UK Biobank）中81718例AIHT病例进行荟萃分析，我们剖析了甲状腺功能障碍和自身免疫轴上的关联。此次迄今为止最大规模的甲状腺功能减退症扫描确定了418个独立关联（p < 5×10），其中一半以上此前未在甲状腺疾病中得到记录。在其中48个关联中，一个蛋白质编码变异是主效单核苷酸多态性（SNP），或者与该基因座的主效SNP高度相关（r > 0.95），包括位于[具体位置1]的低频编码变异以及位于[具体位置2]和[具体位置3]的已确定变异。位于[具体基因1]（P67T）、[具体基因2]（T155M）和[具体基因3]（Q655X）的变异在芬兰高度富集，T细胞功能实验表明，[具体基因2]的T155M等位基因会降低T细胞活化。通过对非甲状腺自身免疫进行大规模扫描以及对促甲状腺激素（TSH）水平进行已发表的荟萃分析，我们使用贝叶斯分类器将相关基因座分解为不同分组，据此估计，相当一部分基因座参与系统性（即普遍涉及多种自身免疫性疾病）自身免疫（34%），另一部分亚组参与甲状腺特异性功能障碍（17%）。通过将这些关联结果与其他常见疾病终点进一步比较，我们发现与皮肤癌存在显著重叠，10%的AIHT基因座呈现出一致但相反的关联模式，即增加甲状腺功能减退症风险的等位基因对皮肤癌具有保护作用。这些关联结果，包括编码检查点抑制剂的基因以及其他影响程序性死亡受体1（PD1）蛋白水平的基因，支持了自身免疫自然变异在影响癌症结局方面的因果作用。
