{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T12:24:28Z","timestamp":1787228668721,"version":"build-2736575974"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":231,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100010256","name":"Guangzhou Municipal Science and Technology Project","doi-asserted-by":"publisher","award":["2024A03J0485"],"award-info":[{"award-number":["2024A03J0485"]}],"id":[{"id":"10.13039\/501100010256","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010256","name":"Guangzhou Municipal Science and Technology Project","doi-asserted-by":"publisher","award":["2025A04J4692"],"award-info":[{"award-number":["2025A04J4692"]}],"id":[{"id":"10.13039\/501100010256","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2021A1515110519"],"award-info":[{"award-number":["2021A1515110519"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Genome\u2010wide association studies (GWAS) have identified over 200 germline risk loci for colorectal cancer (CRC), yet the causal variants and genes behind most GWAS signals remain unknown and the link between inherited risk and tumor outcome is largely unexplored. Connecting germline single nucleotide polymorphisms (SNPs) to gene expression through expression quantitative trait loci (eQTL) and to clinical outcome is needed to interpret this inherited risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We combined CRC GWAS summary data (73,149 cases and 112,467 controls of European ancestry) with GTEx v8 eQTL from colon sigmoid, colon transverse, small intestine terminal ileum, and whole blood, integrating causal transcriptome\u2010wide association study (cTWAS) with SuSiE fine\u2010mapping, Bayesian colocalization, MAGMA SNP\u2010to\u2010gene analysis, and AlphaGenome variant\u2010effect prediction. Prioritized proteins were assessed by western blot. Four experimentally selected regulatory variants were genotyped in HCT116, SW480, RKO, and NCM460 cells; genotype\u2010protein associations were tested across cell\u2010line means, and cis\u2010regulatory effects were assessed by allele\u2010specific expression (ASE) and reference\u2010versus\u2010alternate dual\u2010luciferase assays. Prognostic relevance was evaluated in TCGA colorectal tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      cTWAS identified seven genes with posterior inclusion probability (PIP) &gt;\u20090.50, and colocalization across 78 gene\u2010tissue pairs revealed 20 associations with PP.H4 &gt; 0.80. Four genes showed convergent evidence: SMAD9 (PIP = 0.916, PP.H4 = 0.981), MAP3K2 (PIP = 0.762, PP.H4 = 0.827), FADS1 (PIP = 0.632, PP.H4 = 0.942), and ACTR1B (PIP = 0.566, PP.H4 = 0.994). All four proteins were reduced in CRC cells. Alt\u2010allele dosage was inversely associated with SMAD9 (Pearson\u2009r = \u22120.985, BH\u2010adjusted\n                      <jats:italic>p<\/jats:italic>\n                      = 0.029) and FADS1 protein abundance (\n                      <jats:italic>r<\/jats:italic>\n                      = \u22120.995, BH\u2010adjusted\n                      <jats:italic>p<\/jats:italic>\n                      = 0.020), but not with MAP3K2 or ACTR1B. Reporter and ASE assays detected the clearest allele\u2010specific effects at SMAD9 and FADS1, whereas MAP3K2 and ACTR1B were null in the tested systems. Lower SMAD9 expression was nominally associated with poorer survival (log \u2212 rank\u2009\n                      <jats:italic>p<\/jats:italic>\n                      = 0.022\u2009to\u20090.050), but these associations did not survive Benjamini\u2013Hochberg correction across 12 tests.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Integrating statistical genetics, regulatory prediction, and locus\u2010directed experiments prioritized SMAD9, MAP3K2, FADS1, and ACTR1B as CRC susceptibility genes. Functional evidence was strongest and most directionally coherent for SMAD9, demonstrated allele\u2010specific but context\u2010dependent regulation at FADS1, and placed experimental bounds on the proposed MAP3K2 and ACTR1B mechanisms.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/5617762","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:31:34Z","timestamp":1787225494000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Germline Variants to Tumor Outcome: GWAS\u2010Based Functional Genomics Prioritizes Colorectal Cancer Susceptibility Genes and Links\n                    <i>SMAD9<\/i>\n                    to Prognosis"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1484-6854","authenticated-orcid":false,"given":"Chengguang","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yetong","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8795-163X","authenticated-orcid":false,"given":"Zhao","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0756-0373","authenticated-orcid":false,"given":"Jiani","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6906-5142","authenticated-orcid":false,"given":"Meng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7907-8885","authenticated-orcid":false,"given":"Jiabao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chulan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlin","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0594-0953","authenticated-orcid":false,"given":"Shanshan","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4993-9234","authenticated-orcid":false,"given":"Fei","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-988X","authenticated-orcid":false,"given":"Side","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-327736"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200007133430201"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01222-9"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0286-6"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09775-w"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01900-w"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.02.008"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(22)00044-9"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3506"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3367"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03621-1"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0385-z"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01648-9"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004383"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009440"},{"key":"e_1_2_12_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008720"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-10014-0"},{"key":"e_1_2_12_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz1776"},{"key":"e_1_2_12_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/rssb.12388"},{"key":"e_1_2_12_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010299"},{"key":"e_1_2_12_23_2","doi-asserted-by":"publis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