Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study

Emilio Ugalde-Morales; Rona Wilf; John Pluta; Alexander Ploner; Mengyao Fan; Mohammad Damra; Katja K Aben; Lynn Anson-Cartwright; Chu Chen; Victoria K Cortessis; Siamak Daneshmand; Alberto Ferlin; Marija Gamulin; Jourik A Gietema; Anna Gonzalez-Niera; Tom Grotmol; Robert J Hamilton; Mark Harland; Trine B Haugen; Russ Hauser; Michelle A T Hildebrandt; Robert Karlsson; Lambertus A Kiemeney; Jung Kim; Davor Lessel; Ragnhild A Lothe; Chey Loveday; Stephen J Chanock; Katherine A McGlynn; Coby Meijer; Kevin T Nead; Jeremie Nsengimana; Maja Popovic; Thorunn Rafnar; Lorenzo Richiardi; Maria S Rocca; Stephen M Schwartz; Rolf I Skotheim; Kari Stefansson; Douglas R Stewart; Clare Turnbull; David J Vaughn; Sofia B Winge; Tongzhang Zheng; Alvaro N Monteiro; Kristian Almstrup; Peter A Kanetsky; Katherine L Nathanson; Fredrik Wiklund; Testicular Cancer Consortium

doi:10.1016/j.ajhg.2025.01.022

Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study

Emilio Ugalde-Morales, Rona Wilf, John Pluta, Alexander Ploner, Mengyao Fan, Mohammad Damra, Katja K Aben, Lynn Anson-Cartwright, Chu Chen, Victoria K Cortessis, Siamak Daneshmand, Alberto Ferlin, Marija Gamulin, Jourik A Gietema, Anna Gonzalez-Niera, Tom Grotmol, Robert J Hamilton, Mark Harland, Trine B Haugen, Russ HauserMichelle A T Hildebrandt, Robert Karlsson, Lambertus A Kiemeney, Jung Kim, Davor Lessel, Ragnhild A Lothe, Chey Loveday, Stephen J Chanock, Katherine A McGlynn, Coby Meijer, Kevin T Nead, Jeremie Nsengimana, Maja Popovic, Thorunn Rafnar, Lorenzo Richiardi, Maria S Rocca, Stephen M Schwartz, Rolf I Skotheim, Kari Stefansson, Douglas R Stewart, Clare Turnbull, David J Vaughn, Sofia B Winge, Tongzhang Zheng, Alvaro N Monteiro, Kristian Almstrup, Peter A Kanetsky, Katherine L Nathanson, Fredrik Wiklund^*, Testicular Cancer Consortium

^*Corresponding author for this work

Department of Growth and Reproduction

3 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Human Genetics
Volume	112
Issue number	3
Pages (from-to)	630-643
Number of pages	14
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2025.01.022
Publication status	Published - 6 Mar 2025

Keywords

Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Neoplasms, Germ Cell and Embryonal/genetics
Polymorphism, Single Nucleotide
Testicular Neoplasms/genetics
Transcriptome
colocalization analysis
testicular germ cell tumors
transcriptome-wide association study

Access to Document

10.1016/j.ajhg.2025.01.022Licence: CC BY

Cite this

Ugalde-Morales, E., Wilf, R., Pluta, J., Ploner, A., Fan, M., Damra, M., Aben, K. K., Anson-Cartwright, L., Chen, C., Cortessis, V. K., Daneshmand, S., Ferlin, A., Gamulin, M., Gietema, J. A., Gonzalez-Niera, A., Grotmol, T., Hamilton, R. J., Harland, M., Haugen, T. B., ... Testicular Cancer Consortium (2025). Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study. American Journal of Human Genetics, 112(3), 630-643. https://doi.org/10.1016/j.ajhg.2025.01.022

Ugalde-Morales, E, Wilf, R, Pluta, J, Ploner, A, Fan, M, Damra, M, Aben, KK, Anson-Cartwright, L, Chen, C, Cortessis, VK, Daneshmand, S, Ferlin, A, Gamulin, M, Gietema, JA, Gonzalez-Niera, A, Grotmol, T, Hamilton, RJ, Harland, M, Haugen, TB, Hauser, R, Hildebrandt, MAT, Karlsson, R, Kiemeney, LA, Kim, J, Lessel, D, Lothe, RA, Loveday, C, Chanock, SJ, McGlynn, KA, Meijer, C, Nead, KT, Nsengimana, J, Popovic, M, Rafnar, T, Richiardi, L, Rocca, MS, Schwartz, SM, Skotheim, RI, Stefansson, K, Stewart, DR, Turnbull, C, Vaughn, DJ, Winge, SB, Zheng, T, Monteiro, AN, Almstrup, K, Kanetsky, PA, Nathanson, KL, Wiklund, F & Testicular Cancer Consortium 2025, 'Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study', American Journal of Human Genetics, vol. 112, no. 3, pp. 630-643. https://doi.org/10.1016/j.ajhg.2025.01.022

@article{46da082a2e7e41c4874ba45d4f0bda49,

title = "Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study",

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.",

keywords = "Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Neoplasms, Germ Cell and Embryonal/genetics, Polymorphism, Single Nucleotide, Testicular Neoplasms/genetics, Transcriptome, colocalization analysis, testicular germ cell tumors, transcriptome-wide association study",

author = "Emilio Ugalde-Morales and Rona Wilf and John Pluta and Alexander Ploner and Mengyao Fan and Mohammad Damra and Aben, \{Katja K\} and Lynn Anson-Cartwright and Chu Chen and Cortessis, \{Victoria K\} and Siamak Daneshmand and Alberto Ferlin and Marija Gamulin and Gietema, \{Jourik A\} and Anna Gonzalez-Niera and Tom Grotmol and Hamilton, \{Robert J\} and Mark Harland and Haugen, \{Trine B\} and Russ Hauser and Hildebrandt, \{Michelle A T\} and Robert Karlsson and Kiemeney, \{Lambertus A\} and Jung Kim and Davor Lessel and Lothe, \{Ragnhild A\} and Chey Loveday and Chanock, \{Stephen J\} and McGlynn, \{Katherine A\} and Coby Meijer and Nead, \{Kevin T\} and Jeremie Nsengimana and Maja Popovic and Thorunn Rafnar and Lorenzo Richiardi and Rocca, \{Maria S\} and Schwartz, \{Stephen M\} and Skotheim, \{Rolf I\} and Kari Stefansson and Stewart, \{Douglas R\} and Clare Turnbull and Vaughn, \{David J\} and Winge, \{Sofia B\} and Tongzhang Zheng and Monteiro, \{Alvaro N\} and Kristian Almstrup and Kanetsky, \{Peter A\} and Nathanson, \{Katherine L\} and Fredrik Wiklund and \{Testicular Cancer Consortium\}",

year = "2025",

month = mar,

day = "6",

doi = "10.1016/j.ajhg.2025.01.022",

language = "English",

volume = "112",

pages = "630--643",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study

AU - Ugalde-Morales, Emilio

AU - Wilf, Rona

AU - Pluta, John

AU - Ploner, Alexander

AU - Fan, Mengyao

AU - Damra, Mohammad

AU - Aben, Katja K

AU - Anson-Cartwright, Lynn

AU - Chen, Chu

AU - Cortessis, Victoria K

AU - Daneshmand, Siamak

AU - Ferlin, Alberto

AU - Gamulin, Marija

AU - Gietema, Jourik A

AU - Gonzalez-Niera, Anna

AU - Grotmol, Tom

AU - Hamilton, Robert J

AU - Harland, Mark

AU - Haugen, Trine B

AU - Hauser, Russ

AU - Hildebrandt, Michelle A T

AU - Karlsson, Robert

AU - Kiemeney, Lambertus A

AU - Kim, Jung

AU - Lessel, Davor

AU - Lothe, Ragnhild A

AU - Loveday, Chey

AU - Chanock, Stephen J

AU - McGlynn, Katherine A

AU - Meijer, Coby

AU - Nead, Kevin T

AU - Nsengimana, Jeremie

AU - Popovic, Maja

AU - Rafnar, Thorunn

AU - Richiardi, Lorenzo

AU - Rocca, Maria S

AU - Schwartz, Stephen M

AU - Skotheim, Rolf I

AU - Stefansson, Kari

AU - Stewart, Douglas R

AU - Turnbull, Clare

AU - Vaughn, David J

AU - Winge, Sofia B

AU - Zheng, Tongzhang

AU - Monteiro, Alvaro N

AU - Almstrup, Kristian

AU - Kanetsky, Peter A

AU - Nathanson, Katherine L

AU - Wiklund, Fredrik

AU - Testicular Cancer Consortium

PY - 2025/3/6

Y1 - 2025/3/6

N2 - 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.

AB - 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.

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Neoplasms, Germ Cell and Embryonal/genetics

KW - Polymorphism, Single Nucleotide

KW - Testicular Neoplasms/genetics

KW - Transcriptome

KW - colocalization analysis

KW - testicular germ cell tumors

KW - transcriptome-wide association study

UR - https://www.scopus.com/pages/publications/85218925401

U2 - 10.1016/j.ajhg.2025.01.022

DO - 10.1016/j.ajhg.2025.01.022

M3 - Journal article

C2 - 39999848

SN - 0002-9297

VL - 112

SP - 630

EP - 643

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this