{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T16:03:24Z","timestamp":1789401804852,"version":"build-2803163510"},"reference-count":36,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int J Immunogenetics"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:bold>Background<\/jats:bold>\n                    : Thyroid diseases, including autoimmune thyroid disease (AITD) and thyroid cancer, are characterized by immune dysregulation, yet the cell type\u2013specific genetic mechanisms underlying these conditions remain poorly understood. Most genome\u2010wide association studies (GWAS) have relied on bulk tissue expression quantitative trait loci (eQTL), which cannot resolve the heterogeneity of immune cell populations.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods<\/jats:bold>\n                    : We performed two\u2010sample Mendelian randomization (MR) analyses using single\u2010cell cis\u2010eQTLs from 14 immune cell subtypes (OneK1K cohort) as instrumental variables against GWAS summary statistics for four thyroid outcomes: autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid cancer and autoimmune thyroiditis. Causal associations were validated through Bayesian colocalization, phenome\u2010wide association analysis (PheWAS) and multi\u2010layered transcriptomic validation encompassing spatial transcriptomics of AITD tissue (GSE248205), bulk RNA\u2010seq of thyroid cancer (GSE3678) and single\u2010cell RNA\u2010seq of thyroid tumours (GSE250521). gsMap spatial LD score regression was applied to map disease heritability onto spatial tissue architecture.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results<\/jats:bold>\n                    : We identified six Bonferroni\u2010significant causal gene\u2013cell type pairs for autoimmune hyperthyroidism, including protective effects of\n                    <jats:italic>ABHD16A<\/jats:italic>\n                    in na\u00efve\/immature B cells (OR\u00a0=\u00a00.440),\n                    <jats:italic>HIST1H3H<\/jats:italic>\n                    in CD8 NC T cells (OR\u00a0=\u00a00.324),\n                    <jats:italic>HMGN4<\/jats:italic>\n                    in NK recruiting cells (OR\u00a0=\u00a00.556) and\n                    <jats:italic>ZKSCAN4<\/jats:italic>\n                    in CD8 S100B T cells (OR\u00a0=\u00a00.427), with five pairs showing strong colocalization (PP.H4 \u2265 86%). Three pairs reached significance for autoimmune hypothyroidism, including a risk association of\n                    <jats:italic>HLA\u2010F<\/jats:italic>\n                    in CD4 NC T cells (OR\u00a0=\u00a01.139). For autoimmune thyroiditis,\n                    <jats:italic>FAM134B\/RETREG1<\/jats:italic>\n                    showed consistent suggestive protective associations across both CD4 and CD8 NC T cells (PP.H4 \u2265 90% for both), suggesting a possible involvement of ER phagy regulation in thyroiditis susceptibility. Thyroid cancer showed a suggestive association with\n                    <jats:italic>HLA\u2010G<\/jats:italic>\n                    in classical monocytes (OR\u00a0=\u00a01.899, PP.H4\u00a0=\u00a053%). Spatial transcriptomic validation demonstrated progressive immune infiltration from control tissue to Graves\u2019 disease to Hashimoto's thyroiditis (7.7%\u201315.7%, 46.1%\u201354.1%, respectively) and strong spatial correlation between target gene expression and corresponding cell type enrichment (e.g., plasma cell\u2013\n                    <jats:italic>HLA\u2010DQB1<\/jats:italic>\n                    :\n                    <jats:italic>r<\/jats:italic>\n                    \u00a0=\u00a00.491,\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 10\n                    <jats:sup>\u2212300<\/jats:sup>\n                    ).\n                    <jats:italic>HLA\u2010G<\/jats:italic>\n                    was independently validated in thyroid cancer bulk (log\n                    <jats:sub>2<\/jats:sub>\n                    fc\u00a0=\u00a00.542,\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a09.51\u00a0\u00d7\u00a010\n                    <jats:sup>\u22123<\/jats:sup>\n                    , AUC\u00a0=\u00a00.857) and single\u2010cell datasets. PheWAS revealed no significant associations detected for the core candidates. gsMap identified significant enrichment of autoimmune hypothyroidism heritability in gastrointestinal tract, adrenal gland and adipose tissue (all Bonferroni\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.002).\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusions<\/jats:bold>\n                    : This study establishes a multi\u2010scale analytical framework integrating cell type\u2010resolved genetic inference with spatial tissue validation, revealing distinct immunogenetic architectures underlying autoimmune versus malignant thyroid disease. Protective genetic programs in autoimmune hyperthyroidism converge on chromatin remodelling (\n                    <jats:italic>HIST1H3H<\/jats:italic>\n                    ,\n                    <jats:italic>HMGN4<\/jats:italic>\n                    ,\n                    <jats:italic>ZKSCAN4<\/jats:italic>\n                    ) and lipid metabolism (\n                    <jats:italic>ABHD16A<\/jats:italic>\n                    ) across lymphocyte subsets, whereas thyroid cancer risk involves immune escape mediated by\n                    <jats:italic>HLA\u2010G<\/jats:italic>\n                    in myeloid cells. The ER\u2010phagy receptor RETREG1 represents a candidate pathway warranting further investigation in autoimmune thyroiditis. These findings provide genetically supported, cell type\u2013specific therapeutic targets and demonstrate a generalizable strategy for dissecting the immune\u2010mediated mechanisms of complex thyroid diseases.\n                  <\/jats:p>","DOI":"10.1111\/iji.70066","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T15:10:45Z","timestamp":1789398645000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell Type\u2013Resolved Causal Inference and Spatial Transcriptomic Integration Reveal Immune\u2010Specific Genetic Drivers of Autoimmune and Malignant Thyroid Disease"],"prefix":"10.1111","author":[{"given":"Chun","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Pharmacy Chongqing Three Gorges Medical College Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine  Chengdu China"},{"name":"Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"issue":"23","key":"e_1_2_13_2_1","doi-asserted-by":"crossref","first-page":"7339","DOI":"10.1007\/s00018-021-03975-8","article-title":"Key Features of the POU Transcription Factor Oct4 from an Evolutionary Perspective","volume":"78","author":"Bakhmet E. 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