{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:30:48Z","timestamp":1786595448455,"version":"build-2736575974"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Individuals with attention-deficit\/hyperactivity disorder (ADHD) show an elevated incidence of non-small cell lung cancer (NSCLC), usually attributed to smoking. Innate immune activation and chronic inflammation are implicated in both, yet whether shared germline genetics include a component statistically independent of the measured current-smoking phenotype, and whether that liability has an innate immune dimension, remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We applied genomic structural equation modelling to GWAS summary statistics to partition genetic covariance into indirect and conditional direct components with respect to measured current smoking. Among twelve psychiatric and personality traits, only ADHD survived FDR and served as the primary exposure; neuroticism was retained as a secondary exploratory indicator. Component statistics underwent gene-level and tissue-enrichment analyses. We estimated ADHD and NSCLC genetic correlations with inflammatory biomarkers, tested the NSCLC signal for innate-pathway enrichment, and examined\n                      <jats:italic>CLPTM1L<\/jats:italic>\n                      response to non-nicotine stress in lung adenocarcinoma cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that\n                      <jats:italic>CLPTM1L<\/jats:italic>\n                      ,\n                      <jats:italic>IREB2<\/jats:italic>\n                      and the chromosome 15q25 nicotinic-receptor cluster were prioritised within a component statistically independent of the measured current-smoking phenotype, corresponding to approximately 38% of the model-based shared genetic covariance, with lung and brain enrichment. Pathway and biomarker analyses suggested an innate immune and inflammatory dimension, but did not establish a mechanism. ADHD and NSCLC were each positively genetically correlated with C-reactive protein (ADHD rg=0.26,\n                      <jats:italic>P=<\/jats:italic>\n                      8.2\u00d710\n                      <jats:sup>-<\/jats:sup>\n                      \u00b9\u00b3; NSCLC rg=0.13,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0074); additional inflammatory-trait comparisons were exploratory. The NSCLC signal showed nominal enrichment of innate pattern-recognition-receptor and NF-\u03baB\/antiviral pathways. In A549 cells,\n                      <jats:italic>CLPTM1L<\/jats:italic>\n                      protein increased under genotoxic and hypoxic stress, with immunofluorescence 3.4-fold and 2.3-fold above control.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      An approximate model-based component of the ADHD\u2013NSCLC genetic covariance was statistically independent of the measured current-smoking phenotype; pathway and biomarker analyses suggested, but did not establish, an innate immune and inflammatory dimension alongside the 15q25 cholinergic axis.\n                      <jats:italic>CLPTM1L<\/jats:italic>\n                      expression was responsive in a non-nicotine pathological cell state, without evidence of mediation or causality. These hypothesis-generating findings nominate innate-immune hypotheses for functional follow-up.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1913958","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:24:36Z","timestamp":1786595076000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ADHD-anchored partitioning of non-small cell lung cancer genetic covariance identifies CLPTM1L and suggestive innate-immune signals"],"prefix":"10.3389","volume":"17","author":[{"given":"Ting","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Radiology, Shanghai Jiaotong University Affiliated Sixth People\u2019s Hospital South Campus","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Practice, Nanqiao Town Community Health Service Center","place":["Fengxian, Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Ultrasonography, Shanghai Eighth People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Radiology, Shanghai Jiaotong University Affiliated Sixth People\u2019s Hospital South Campus","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Shanghai Jiaotong University Affiliated Sixth People\u2019s Hospital South Campus","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Shanghai Jiaotong University Affiliated Sixth People\u2019s Hospital South Campus","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinglin","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Respiratory Center, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoling","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ultrasonography, Shanghai Eighth People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibiao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Shanghai Jiaotong University Affiliated Sixth People\u2019s Hospital South 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