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3. Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Author

Chen, Zhishan, Guo, Xingyi, Tao, Ran, Huyghe, Jeroen R., Law, Philip J., Fernandez-Rozadilla, Ceres, Ping, Jie, Jia, Guochong, Long, Jirong, Li, Chao, Shen, Quanhu, Xie, Yuhan, Timofeeva, Maria N., Thomas, Minta, Schmit, Stephanie L., Díez-Obrero, Virginia, Devall, Matthew, Moratalla-Navarro, Ferran, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah E. W., Svinti, Victoria, Donnelly, Kevin, Farrington, Susan M., Blackmur, James, Vaughan-Shaw, Peter G., Shu, Xiao-Ou, Lu, Yingchang, Broderick, Peter, Studd, James, Harrison, Tabitha A., Conti, David V., Schumacher, Fredrick R., Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Oh, Jae Hwan, Kim, Jeongseon, Jee, Sun Ha, Jung, Keum Ji, Kweon, Sun-Seog, Shin, Min-Ho, Shin, Aesun, Ahn, Yoon-Ok, Kim, Dong-Hyun, Oze, Isao, Wen, Wanqing, Matsuo, Keitaro, Matsuda, Koichi, Tanikawa, Chizu, Ren, Zefang, Gao, Yu-Tang, Jia, Wei-Hua, Hopper, John L., Jenkins, Mark A., Win, Aung Ko, Pai, Rish K., Figueiredo, Jane C., Haile, Robert W., Gallinger, Steven, Woods, Michael O., Newcomb, Polly A., Duggan, David, Cheadle, Jeremy P., Kaplan, Richard, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Jukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri A., Rissanen, Harri, Pukkala, Eero, Eriksson, Johan G., Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie J., Ruiz-Narvaez, Edward, Palmer, Julie R., Buchanan, Daniel D., Platz, Elizabeth A., Visvanathan, Kala, Ulrich, Cornelia M., Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter T., Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha L., Potter, John D., Tsilidis, Kostas K., Schulze, Matthias B., Gunter, Marc J., Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Bishop, D. Timothy, Giles, Graham G., Southey, Melissa C., Idos, Gregory E., McDonnell, Kevin J., Abu-Ful, Zomoroda, Greenson, Joel K., Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope O., van Guelpen, Bethany, Hudson, Thomas J., Hampel, Heather, Pearlman, Rachel, Berndt, Sonja I., Hayes, Richard B., Martinez, Marie Elena, Thomas, Sushma S., Pharoah, Paul D. P., Larsson, Susanna C., Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly F., Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew T., Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David J., Joshi, Amit D., Schafmayer, Clemens, Scacheri, Peter C., Kundaje, Anshul, Schoen, Robert E., Hampe, Jochen, Stadler, Zsofia K., Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Edlund, Christopher K., Gauderman, W. James, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen J., van Duijnhoven, Franzel, Feskens, Edith J. M., Sakoda, Lori C., Gago-Dominguez, Manuela, Wolk, Alicja, Pardini, Barbara, FitzGerald, Liesel M., Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie A., Kooperberg, Charles, Li, Christopher I., Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Le Marchand, Loic, Wu, Anna H., Qu, Chenxu, McNeil, Caroline E., Coetzee, Gerhard, Hayward, Caroline, Deary, Ian J., Harris, Sarah E., Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Lau, Ken S., Zhao, Hongyu, Hsu, Li, Cai, Qiuyin, Dunlop, Malcolm G., Gruber, Stephen B., Houlston, Richard S., Moreno, Victor, Casey, Graham, Peters, Ulrike, Tomlinson, Ian, and Zheng, Wei

Published
2024
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6. Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Author

Thomas, Minta, Su, Yu-Ru, Rosenthal, Elisabeth A., Sakoda, Lori C., Schmit, Stephanie L., Timofeeva, Maria N., Chen, Zhishan, Fernandez-Rozadilla, Ceres, Law, Philip J., Murphy, Neil, Carreras-Torres, Robert, Diez-Obrero, Virginia, van Duijnhoven, Franzel J. B., Jiang, Shangqing, Shin, Aesun, Wolk, Alicja, Phipps, Amanda I., Burnett-Hartman, Andrea, Gsur, Andrea, Chan, Andrew T., Zauber, Ann G., Wu, Anna H., Lindblom, Annika, Um, Caroline Y., Tangen, Catherine M., Gignoux, Chris, Newton, Christina, Haiman, Christopher A., Qu, Conghui, Bishop, D. Timothy, Buchanan, Daniel D., Crosslin, David R., Conti, David V., Kim, Dong-Hyun, Hauser, Elizabeth, White, Emily, Siegel, Erin, Schumacher, Fredrick R., Rennert, Gad, Giles, Graham G., Hampel, Heather, Brenner, Hermann, Oze, Isao, Oh, Jae Hwan, Lee, Jeffrey K., Schneider, Jennifer L., Chang-Claude, Jenny, Kim, Jeongseon, Huyghe, Jeroen R., Zheng, Jiayin, Hampe, Jochen, Greenson, Joel, Hopper, John L., Palmer, Julie R., Visvanathan, Kala, Matsuo, Keitaro, Matsuda, Koichi, Jung, Keum Ji, Li, Li, Le Marchand, Loic, Vodickova, Ludmila, Bujanda, Luis, Gunter, Marc J., Matejcic, Marco, Jenkins, Mark A., Slattery, Martha L., D’Amato, Mauro, Wang, Meilin, Hoffmeister, Michael, Woods, Michael O., Kim, Michelle, Song, Mingyang, Iwasaki, Motoki, Du, Mulong, Udaltsova, Natalia, Sawada, Norie, Vodicka, Pavel, Campbell, Peter T., Newcomb, Polly A., Cai, Qiuyin, Pearlman, Rachel, Pai, Rish K., Schoen, Robert E., Steinfelder, Robert S., Haile, Robert W., Vandenputtelaar, Rosita, Prentice, Ross L., Küry, Sébastien, Castellví-Bel, Sergi, Tsugane, Shoichiro, Berndt, Sonja I., Lee, Soo Chin, Brezina, Stefanie, Weinstein, Stephanie J., Chanock, Stephen J., Jee, Sun Ha, Kweon, Sun-Seog, Vadaparampil, Susan, Harrison, Tabitha A., Yamaji, Taiki, Keku, Temitope O., Vymetalkova, Veronika, Arndt, Volker, Jia, Wei-Hua, Shu, Xiao-Ou, Lin, Yi, Ahn, Yoon-Ok, Stadler, Zsofia K., Van Guelpen, Bethany, Ulrich, Cornelia M., Platz, Elizabeth A., Potter, John D., Li, Christopher I., Meester, Reinier, Moreno, Victor, Figueiredo, Jane C., Casey, Graham, Lansdorp Vogelaar, Iris, Dunlop, Malcolm G., Gruber, Stephen B., Hayes, Richard B., Pharoah, Paul D. P., Houlston, Richard S., Jarvik, Gail P., Tomlinson, Ian P., Zheng, Wei, Corley, Douglas A., Peters, Ulrike, and Hsu, Li

Published
2023
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9. Systematic investigation of genetically determined plasma and urinary metabolites to discover potential interventional targets for colorectal cancer

Author

Sun, Jing, Zhao, Jianhui, Zhou, Siyun, Li, Xinxuan, Li, Tengfei, Wang, Lijuan, Yuan, Shuai, Chen, Dong, Law, Philip J., Larsson, Susanna C., Farrington, Susan M., Houlston, Richard S., Dunlop, Malcolm G., Theodoratou, Evropi, Li, Xue, Sun, Jing, Zhao, Jianhui, Zhou, Siyun, Li, Xinxuan, Li, Tengfei, Wang, Lijuan, Yuan, Shuai, Chen, Dong, Law, Philip J., Larsson, Susanna C., Farrington, Susan M., Houlston, Richard S., Dunlop, Malcolm G., Theodoratou, Evropi, and Li, Xue

Abstract

Background We aimed to identify plasma and urinary metabolites related to colorectal cancer (CRC) risk and elucidate their mediator role in the associations between modifiable risk factors and CRC.Methods Metabolite quantitative trait loci were derived from 2 published metabolomics genome-wide association studies, and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale genome-wide association study meta-analysis (100 204 cases, 154 587 controls) and the FinnGen cohort (4957 cases, 304 197 controls). Mendelian randomization and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable Mendelian randomization and mediation estimation were conducted to elucidate the mediating effects of metabolites on the associations between modifiable risk factors and CRC.Results The study identified 30 plasma metabolites and 4 urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, olipudase alfa, tilactase). Thirteen modifiable risk factors were associated with 9 metabolites, and 8 of these modifiable risk factors were associated with CRC risk. These 9 metabolites mediated the effect of modifiable risk factors (Actinobacteria, body mass index, waist to hip ratio, fasting insulin, smoking initiation) on CRC.Conclusion This study identified key metabolite biomarkers associated with CRC and elucidated their mediator roles in the associations between modifiable risk factors and CRC. These findings provide new insights into the etiology and potential therapeutic targets for CRC and the etiological pathways of modifiable environmental factors with CRC.

Published
2024
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10. Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Author

Chen, Zhishan, Guo, Xingyi, Tao, Ran, Huyghe, Jeroen R., Law, Philip J., Fernandez-Rozadilla, Ceres, Ping, Jie, Jia, Guochong, Long, Jirong, Li, Chao, Shen, Quanhu, Xie, Yuhan, Timofeeva, Maria N., Thomas, Minta, Schmit, Stephanie L., Díez-Obrero, Virginia, Devall, Matthew, Moratalla-Navarro, Ferran, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah E. W., Svinti, Victoria, Donnelly, Kevin, Farrington, Susan M., Blackmur, James, Vaughan-Shaw, Peter G., Shu, Xiao-Ou, Lu, Yingchang, Broderick, Peter, Studd, James, Harrison, Tabitha A., Conti, David V., Schumacher, Fredrick R., Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Oh, Jae Hwan, Kim, Jeongseon, Jee, Sun Ha, Jung, Keum Ji, Kweon, Sun-Seog, Shin, Min-Ho, Shin, Aesun, Ahn, Yoon-Ok, Kim, Dong-Hyun, Oze, Isao, Wen, Wanqing, Matsuo, Keitaro, Matsuda, Koichi, Tanikawa, Chizu, Ren, Zefang, Gao, Yu-Tang, Jia, Wei-Hua, Hopper, John L., Jenkins, Mark A., Win, Aung Ko, Pai, Rish K., Figueiredo, Jane C., Haile, Robert W., Gallinger, Steven, Woods, Michael O., Newcomb, Polly A., Duggan, David, Cheadle, Jeremy P., Kaplan, Richard, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Jukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri A., Rissanen, Harri, Pukkala, Eero, Eriksson, Johan G., Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie J., Ruiz-Narvaez, Edward, Palmer, Julie R., Buchanan, Daniel D., Platz, Elizabeth A., Visvanathan, Kala, Ulrich, Cornelia M., Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter T., Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha L., Potter, John D., Tsilidis, Kostas K., Schulze, Matthias B., Gunter, Marc J., Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Bishop, D. Timothy, Giles, Graham G., Southey, Melissa C., Idos, Gregory E., McDonnell, Kevin J., Abu-Ful, Zomoroda, Greenson, Joel K., Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope O., van Guelpen, Bethany, Hudson, Thomas J., Hampel, Heather, Pearlman, Rachel, Berndt, Sonja I., Hayes, Richard B., Martinez, Marie Elena, Thomas, Sushma S., Pharoah, Paul D. P., Larsson, Susanna C., Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly F., Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew T., Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David J., Joshi, Amit D., Schafmayer, Clemens, Scacheri, Peter C., Kundaje, Anshul, Schoen, Robert E., Hampe, Jochen, Stadler, Zsofia K., Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Edlund, Christopher K., Gauderman, W. James, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen J., van Duijnhoven, Franzel, Feskens, Edith J. M., Sakoda, Lori C., Gago-Dominguez, Manuela, Wolk, Alicja, Pardini, Barbara, FitzGerald, Liesel M., Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie A., Kooperberg, Charles, Li, Christopher I., Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Le Marchand, Loic, Wu, Anna H., Qu, Chenxu, McNeil, Caroline E., Coetzee, Gerhard, Hayward, Caroline, Deary, Ian J., Harris, Sarah E., Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Lau, Ken S., Zhao, Hongyu, Hsu, Li, Cai, Qiuyin, Dunlop, Malcolm G., Gruber, Stephen B., Houlston, Richard S., Moreno, Victor, Casey, Graham, Peters, Ulrike, Tomlinson, Ian, Zheng, Wei, Chen, Zhishan, Guo, Xingyi, Tao, Ran, Huyghe, Jeroen R., Law, Philip J., Fernandez-Rozadilla, Ceres, Ping, Jie, Jia, Guochong, Long, Jirong, Li, Chao, Shen, Quanhu, Xie, Yuhan, Timofeeva, Maria N., Thomas, Minta, Schmit, Stephanie L., Díez-Obrero, Virginia, Devall, Matthew, Moratalla-Navarro, Ferran, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah E. W., Svinti, Victoria, Donnelly, Kevin, Farrington, Susan M., Blackmur, James, Vaughan-Shaw, Peter G., Shu, Xiao-Ou, Lu, Yingchang, Broderick, Peter, Studd, James, Harrison, Tabitha A., Conti, David V., Schumacher, Fredrick R., Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Oh, Jae Hwan, Kim, Jeongseon, Jee, Sun Ha, Jung, Keum Ji, Kweon, Sun-Seog, Shin, Min-Ho, Shin, Aesun, Ahn, Yoon-Ok, Kim, Dong-Hyun, Oze, Isao, Wen, Wanqing, Matsuo, Keitaro, Matsuda, Koichi, Tanikawa, Chizu, Ren, Zefang, Gao, Yu-Tang, Jia, Wei-Hua, Hopper, John L., Jenkins, Mark A., Win, Aung Ko, Pai, Rish K., Figueiredo, Jane C., Haile, Robert W., Gallinger, Steven, Woods, Michael O., Newcomb, Polly A., Duggan, David, Cheadle, Jeremy P., Kaplan, Richard, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Jukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri A., Rissanen, Harri, Pukkala, Eero, Eriksson, Johan G., Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie J., Ruiz-Narvaez, Edward, Palmer, Julie R., Buchanan, Daniel D., Platz, Elizabeth A., Visvanathan, Kala, Ulrich, Cornelia M., Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter T., Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha L., Potter, John D., Tsilidis, Kostas K., Schulze, Matthias B., Gunter, Marc J., Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Bishop, D. Timothy, Giles, Graham G., Southey, Melissa C., Idos, Gregory E., McDonnell, Kevin J., Abu-Ful, Zomoroda, Greenson, Joel K., Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope O., van Guelpen, Bethany, Hudson, Thomas J., Hampel, Heather, Pearlman, Rachel, Berndt, Sonja I., Hayes, Richard B., Martinez, Marie Elena, Thomas, Sushma S., Pharoah, Paul D. P., Larsson, Susanna C., Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly F., Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew T., Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David J., Joshi, Amit D., Schafmayer, Clemens, Scacheri, Peter C., Kundaje, Anshul, Schoen, Robert E., Hampe, Jochen, Stadler, Zsofia K., Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Edlund, Christopher K., Gauderman, W. James, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen J., van Duijnhoven, Franzel, Feskens, Edith J. M., Sakoda, Lori C., Gago-Dominguez, Manuela, Wolk, Alicja, Pardini, Barbara, FitzGerald, Liesel M., Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie A., Kooperberg, Charles, Li, Christopher I., Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Le Marchand, Loic, Wu, Anna H., Qu, Chenxu, McNeil, Caroline E., Coetzee, Gerhard, Hayward, Caroline, Deary, Ian J., Harris, Sarah E., Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Lau, Ken S., Zhao, Hongyu, Hsu, Li, Cai, Qiuyin, Dunlop, Malcolm G., Gruber, Stephen B., Houlston, Richard S., Moreno, Victor, Casey, Graham, Peters, Ulrike, Tomlinson, Ian, and Zheng, Wei

Abstract

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Published
2024
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11. Combining Asian-European Genome-Wide Association Studies of Colorectal Cancer Improves Risk Prediction Across Race and Ethnicity

Author

Thomas, Minta, primary, Su, Yu-Ru, additional, Rosenthal, Elisabeth A., additional, Sakoda, Lori C, additional, Schmit, Stephanie L, additional, Timofeeva, Maria N, additional, Chen, Zhishan, additional, Fernandez-Rozadilla, Ceres, additional, Law, Philip J, additional, Murphy, Neil, additional, Carreras-Torres, Robert, additional, Diez-Obrero, Virginia, additional, van Duijnhoven, Franzel JB, additional, Jiang, Shangqing, additional, Shin, Aesun, additional, Wolk, Alicja, additional, Phipps, Amanda I, additional, Burnett-Hartman, Andrea, additional, Gsur, Andrea, additional, Chan, Andrew T, additional, Zauber, Ann G, additional, Wu, Anna H, additional, Lindblom, Annika, additional, Um, Caroline Y, additional, Tangen, Catherine M, additional, Gignoux, Chris, additional, Newton, Christina, additional, Haiman, Christopher A., additional, Qu, Conghui, additional, Bishop, D Timothy, additional, Buchanan, Daniel D, additional, Crosslin, David R., additional, Conti, David V, additional, Kim, Dong-Hyun, additional, Hauser, Elizabeth, additional, White, Emily, additional, Siegel, Erin, additional, Schumacher, Fredrick R, additional, Rennert, Gad, additional, Giles, Graham G, additional, Hampel, Heather, additional, Brenner, Hermann, additional, Oze, Isao, additional, Oh, Jae Hwan, additional, Lee, Jeffrey K, additional, Schneider, Jennifer L, additional, Chang-Claude, Jenny, additional, Kim, Jeongseon, additional, Huyghe, Jeroen R, additional, Zheng, Jiayin, additional, Hampe, Jochen, additional, Greenson, Joel, additional, Hopper, John L, additional, Palmer, Julie R, additional, Visvanathan, Kala, additional, Matsuo, Keitaro, additional, Matsuda, Koichi, additional, Jung, Keum Ji, additional, Li, Li, additional, Marchand, Loic Le, additional, Vodickova, Ludmila, additional, Bujanda, Luis, additional, Gunter, Marc J, additional, Matejcic, Marco, additional, Jenkins, Mark A, additional, Slattery, Martha L, additional, D’Amato, Mauro, additional, Wang, Meilin, additional, Hoffmeister, Michael, additional, Woods, Michael O, additional, Kim, Michelle, additional, Song, Mingyang, additional, Iwasaki, Motoki, additional, Du, Mulong, additional, Udaltsova, Natalia, additional, Sawada, Norie, additional, Vodicka, Pavel, additional, Campbell, Peter T, additional, Newcomb, Polly A, additional, Cai, Qiuyin, additional, Pearlman, Rachel, additional, Pai, Rish K, additional, Schoen, Robert E, additional, Steinfelder, Robert S, additional, Haile, Robert W, additional, Vandenputtelaar, Rosita, additional, Prentice, Ross L, additional, Küry, Sébastien, additional, Castellví-Bel, Sergi, additional, Tsugane, Shoichiro, additional, Berndt, Sonja I, additional, Lee, Soo Chin, additional, Brezina, Stefanie, additional, Weinstein, Stephanie J, additional, Chanock, Stephen J, additional, Jee, Sun Ha, additional, Kweon, Sun-Seog, additional, Vadaparampil, Susan, additional, Harrison, Tabitha A, additional, Yamaji, Taiki, additional, Keku, Temitope O, additional, Vymetalkova, Veronika, additional, Arndt, Volker, additional, Jia, Wei-Hua, additional, Shu, Xiao-Ou, additional, Lin, Yi, additional, Ahn, Yoon-Ok, additional, Stadler, Zsofia K, additional, Van Guelpen, Bethany, additional, Ulrich, Cornelia M, additional, Platz, Elizabeth A, additional, Potter, John D, additional, Li, Christopher I, additional, Meester, Reinier, additional, Moreno, Victor, additional, Figueiredo, Jane C, additional, Casey, Graham, additional, Vogelaar, Iris Landorp, additional, Dunlop, Malcolm G, additional, Gruber, Stephen B, additional, Hayes, Richard B, additional, Pharoah, Paul D P, additional, Houlston, Richard S, additional, Jarvik, Gail P, additional, Tomlinson, Ian P, additional, Zheng, Wei, additional, Corley, Douglas A, additional, Peters, Ulrike, additional, and Hsu, Li, additional

Published
2023
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12. Genetically proxied ketohexokinase function and risk of colorectal cancer: a Mendelian randomisation study

Author

Buziau, Amée M, primary, Law, Philip J, additional, Blokland, Gabriella, additional, Schalkwijk, Casper, additional, Scheijen, Jean, additional, Simons, Pomme, additional, van der Kallen, Carla, additional, Eussen, Simone, additional, Dagnelie, Pieter C, additional, van Greevenbroek, Marleen, additional, Houlston, Richard S, additional, Wesselius, Anke, additional, Went, Molly, additional, Stehouwer, Coen, additional, and Brouwers, Martijn CGJ, additional

Published
2022
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13. Alcohol consumption, DNA methylation and colorectal cancer risk: Results from pooled cohort studies and Mendelian randomization analysis.

Author

Zhou, Xuan, Wang, Lijuan, Xiao, Jiarui, Sun, Jing, Yu, Lili, Zhang, Han, Meng, Xiangrui, Yuan, Shuai, Timofeeva, Maria, Law, Philip J., Houlston, Richard S., Ding, Kefeng, Dunlop, Malcolm G., Theodoratou, Evropi, and Li, Xue

Subjects
ALCOHOL drinking, DNA methylation, COLORECTAL cancer, DISEASE risk factors, COHORT analysis, METHYLATION, EPIGENOMICS
Abstract

Alcohol consumption is thought to be one of the modifiable risk factors for colorectal cancer (CRC). However, the causality and mechanisms by which alcohol exerts its carcinogenic effect are unclear. We evaluated the association between alcohol consumption and CRC risk by analyzing data from 32 cohort studies and conducted two‐sample Mendelian randomization (MR) analysis to examine for casual relationship. To explore the effect of alcohol related DNA methylation on CRC risk, we performed an epigenetic MR analysis with data from an epigenome‐wide association study (EWAS). We additionally performed gene‐alcohol interaction analysis nested in the UK Biobank to assess effect modification between alcohol consumption and susceptibility genes. We discovered distinct effects of alcohol on CRC incidence and mortality from the meta‐analyses, and genetic predisposition to alcohol drinking was causally associated with an increased CRC risk (OR = 1.79, 95% CI: 1.23‐2.61) using two‐sample MR approaches. In epigenetic MR analysis, two alcohol‐related CpG sites (cg05593667 and cg10045354 mapped to COLCA1/COLCA2 gene) were identified causally associated with an increased CRC risk (P < 8.20 × 10−4). Gene‐alcohol interaction analysis revealed that carriage of the risk allele of the eQTL (rs3087967) and mQTL (rs11213823) polymorphism of COLCA1/COLCA2 would interact with alcohol consumption to increase CRC risk (PInteraction =.027 and PInteraction =.016). Our study provides comprehensive evidence to elucidate the role of alcohol in CRC and highlights that the pathogenic effect of alcohol on CRC could be partly attributed to DNA methylation by regulating the expression of COLCA1/COLCA2 gene. [ABSTRACT FROM AUTHOR]

Published
2022
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14. Genetically proxied ketohexokinase function and risk of colorectal cancer: a Mendelian randomisation study.

Author

Buziau, Amée M., Law, Philip J., Blokland, Gabriella, Schalkwijk, Casper, Scheijen, Jean, Simons, Pomme, van der Kallen, Carla, Eussen, Simone, Dagnelie, Pieter C., van Greevenbroek, Marleen, Houlston, Richard S., Wesselius, Anke, Went, Molly, Stehouwer, Coen, and Brouwers, Martijn C. G. J.

Subjects
GASTROINTESTINAL hemorrhage, COLORECTAL cancer, DISEASE risk factors, FATTY liver
Published
2023
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16. Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator POU2AF2 .

Author

Rajasekaran V, Harris BT, Osborn RT, Smillie C, Donnelly K, Bacou M, Esiri-Bloom E, Ooi LY, Allan M, Walker M, Reid S, Meynert A, Grimes G, Blackmur JP, Vaughan-Shaw PG, Law PJ, Fernández-Rozadilla C, Tomlinson I, Houlston RS, Myant KB, Din FV, Timofeeva M, Dunlop MG, and Farrington SM

Abstract

Background: Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on POU2AF2 , COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk., Objective: Undertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk., Design: We employ analysis of RNA sequencing, single-cell RNA sequencing, chromatin immunoprecipitation sequencing and single-cell ATAC sequencing data to identify, prioritise and characterise the genes that contribute to CRC risk. We further validate these findings using mouse models and demonstrate parallel effects in human colonic mucosa., Results: We establish rs3087967 as a prime eQTL variant at 11q23.1, colocalising with CRC risk. Furthermore, rs3087967 influences expression of 21 distant genes, thereby acting as a trans-eQTL hub for a gene-set highly enriched for tuft cell markers. Epigenomic analysis implicates POU2AF2 as controlling the tuft cell-specific trans-genes, through POU2F3-correlated genomic regulation. Immunofluorescence confirms rs3087967 risk genotype (T) to be associated with a tuft cell deficit in the human colon. CRISPR-mediated deletion of the 11q23.1 risk locus genes in the mouse germline exacerbated the Apc Min/+ mouse phenotype on abrogation of Pou2af2 expression specifically., Conclusion: We demonstrate that genotype at rs3087967 controls a portfolio of genes through misregulation of POU2AF2. POU2AF2 is the primary transcriptional activator of tuft cells with a tumour suppressive role in mouse models. We therefore implicate tuft cells as having a key tumour-protective role in the large bowel epithelium., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Published
2024
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17. Combining Asian-European Genome-Wide Association Studies of Colorectal Cancer Improves Risk Prediction Across Race and Ethnicity.

Author

Thomas M, Su YR, Rosenthal EA, Sakoda LC, Schmit SL, Timofeeva MN, Chen Z, Fernandez-Rozadilla C, Law PJ, Murphy N, Carreras-Torres R, Diez-Obrero V, van Duijnhoven FJ, Jiang S, Shin A, Wolk A, Phipps AI, Burnett-Hartman A, Gsur A, Chan AT, Zauber AG, Wu AH, Lindblom A, Um CY, Tangen CM, Gignoux C, Newton C, Haiman CA, Qu C, Bishop DT, Buchanan DD, Crosslin DR, Conti DV, Kim DH, Hauser E, White E, Siegel E, Schumacher FR, Rennert G, Giles GG, Hampel H, Brenner H, Oze I, Oh JH, Lee JK, Schneider JL, Chang-Claude J, Kim J, Huyghe JR, Zheng J, Hampe J, Greenson J, Hopper JL, Palmer JR, Visvanathan K, Matsuo K, Matsuda K, Jung KJ, Li L, Marchand LL, Vodickova L, Bujanda L, Gunter MJ, Matejcic M, Jenkins MA, Slattery ML, D'Amato M, Wang M, Hoffmeister M, Woods MO, Kim M, Song M, Iwasaki M, Du M, Udaltsova N, Sawada N, Vodicka P, Campbell PT, Newcomb PA, Cai Q, Pearlman R, Pai RK, Schoen RE, Steinfelder RS, Haile RW, Vandenputtelaar R, Prentice RL, Küry S, Castellví-Bel S, Tsugane S, Berndt SI, Lee SC, Brezina S, Weinstein SJ, Chanock SJ, Jee SH, Kweon SS, Vadaparampil S, Harrison TA, Yamaji T, Keku TO, Vymetalkova V, Arndt V, Jia WH, Shu XO, Lin Y, Ahn YO, Stadler ZK, Van Guelpen B, Ulrich CM, Platz EA, Potter JD, Li CI, Meester R, Moreno V, Figueiredo JC, Casey G, Vogelaar IL, Dunlop MG, Gruber SB, Hayes RB, Pharoah PDP, Houlston RS, Jarvik GP, Tomlinson IP, Zheng W, Corley DA, Peters U, and Hsu L

Abstract

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Published
2023
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