Ugalde-Morales, Emilio and Wilf, Rona and Pluta, John and Ploner, Alexander and Fan, Mengyao and Damra, Mohammad and Aben, Katja K. and Anson-Cartwright, Lynn and Chen, Chu and Cortessis, Victoria K. and Daneshmand, Siamak and Ferlin, Alberto and Gamulin, Marija and Gietema, Jourik A. and Gonzalez-Niera, Anna and Grotmol, Tom and Hamilton, Robert J. and Harland, Mark and Haugen, Trine B. and Hauser, Russ and Hildebrandt, Michelle A. T. and Karlsson, Robert and Kiemeney, Lambertus A. and Kim, Jung and Lessel, Davor and Lothe, Ragnhild A. and Loveday, Chey and Chanock, Stephen J. and Mcglynn, Katherine A. and Meijer, Coby and Nead, Kevin T. and Nsengimana, Jeremie and Popovic, Maja and Rafnar, Thorunn and Richiardi, Lorenzo and Rocca, Maria S. and Schwartz, Stephen M. and Skotheim, Rolf I. and Stefansson, Kari and Stewart, Douglas R. and Turnbull, Clare and Vaughn, David J. and Winge, Sofia B. and Zheng, Tongzhang and Monteiro, Alvaro N. and Almstrup, Kristian and Kanetsky, Peter A. and Nathanson, Katherine L. and Wiklund, Fredrik (2025) Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study. AMERICAN JOURNAL OF HUMAN GENETICS, 112 (3). pp. 630-643. ISSN 0002-9297, 1537-6605
Full text not available from this repository. (Request a copy)Abstract
Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis tested 19,805 gene- disease links, revealing 165 TGCT-associated genes with a false discovery rate of less than 0.01. We prioritized 46 candidate genes by considering GWAS-inflated signals, correlations between neighboring genes, and evidence of colocalization. Among these, 23 genes overlap with 22 GWAS loci, with 7 being associations not previously implicated in TGCT risk. Additionally, 23 genes located within 21 loci are at least 1 Mb away from published GWAS index variants. The 46 prioritized genes display expression levels consistent with expected expression levels in human gonadal cell types and precursor tumor cells and significant enrichment in TGCTs. Additionally, immunohistochemistry revealed protein-level accumulation of two candidate genes, ARID3B and GINM1, in both precursor and tumor cells. These findings enhance our understanding of the genetic predisposition to TGCTs and underscore the importance of further functional investigations into these candidate genes.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CANCER; LOCI; EXPRESSION; TWINS; METAANALYSIS; POPULATIONS; VARIANTS; ARID3B; DMRT1; RISKS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Apr 2026 08:29 |
| Last Modified: | 01 Apr 2026 08:29 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67771 |
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