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145 results on '"Gauderman, W James"'

1. Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer

Author: Drew, David A., Kim, Andre E., Lin, Yi, Qu, Conghui, Morrison, John, Lewinger, Juan Pablo, Kawaguchi, Eric, Wang, Jun, Fu, Yubo, Zemlianskaia, Natalia, Díez-Obrero, Virginia, Bien, Stephanie A., Dimou, Niki, Albanes, Demetrius, Baurley, James W., Wu, Anna H., Buchanan, Daniel D., Potter, John D., Prentice, Ross L., Harlid, Sophia, Arndt, Volker, Barry, Elizabeth L., Berndt, Sonja I., Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chang-Claude, Jenny, Conti, David V., Devall, Matthew A M, Figueiredo, Jane C., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kundaje, Anshul, Le Marchand, Loic, Li, Li, Lynch, Brigid M., Murphy, Neil, Nassir, Rami, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Stern, Mariana C., Su, Yu-Ru, Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, White, Emily, Hsu, Li, Moreno, Victor, Peters, Ulrike, Chan, Andrew T., Gauderman, W James, Drew, David A., Kim, Andre E., Lin, Yi, Qu, Conghui, Morrison, John, Lewinger, Juan Pablo, Kawaguchi, Eric, Wang, Jun, Fu, Yubo, Zemlianskaia, Natalia, Díez-Obrero, Virginia, Bien, Stephanie A., Dimou, Niki, Albanes, Demetrius, Baurley, James W., Wu, Anna H., Buchanan, Daniel D., Potter, John D., Prentice, Ross L., Harlid, Sophia, Arndt, Volker, Barry, Elizabeth L., Berndt, Sonja I., Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chang-Claude, Jenny, Conti, David V., Devall, Matthew A M, Figueiredo, Jane C., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kundaje, Anshul, Le Marchand, Loic, Li, Li, Lynch, Brigid M., Murphy, Neil, Nassir, Rami, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Stern, Mariana C., Su, Yu-Ru, Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, White, Emily, Hsu, Li, Moreno, Victor, Peters, Ulrike, Chan, Andrew T., and Gauderman, W James
Abstract: Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
Published: 2024
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2. Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer

Author: Drew, David A., Kim, Andre E., Lin, Yi, Qu, Conghui, Morrison, John, Lewinger, Juan Pablo, Kawaguchi, Eric, Wang, Jun, Fu, Yubo, Zemlianskaia, Natalia, Díez-Obrero, Virginia, Bien, Stephanie A., Dimou, Niki, Albanes, Demetrius, Baurley, James W., Wu, Anna H., Buchanan, Daniel D., Potter, John D., Prentice, Ross L., Harlid, Sophia, Arndt, Volker, Barry, Elizabeth L., Berndt, Sonja I., Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chang-Claude, Jenny, Conti, David V., Devall, Matthew A M, Figueiredo, Jane C., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kundaje, Anshul, Le Marchand, Loic, Li, Li, Lynch, Brigid M., Murphy, Neil, Nassir, Rami, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Stern, Mariana C., Su, Yu-Ru, Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, White, Emily, Hsu, Li, Moreno, Victor, Peters, Ulrike, Chan, Andrew T., Gauderman, W James, Drew, David A., Kim, Andre E., Lin, Yi, Qu, Conghui, Morrison, John, Lewinger, Juan Pablo, Kawaguchi, Eric, Wang, Jun, Fu, Yubo, Zemlianskaia, Natalia, Díez-Obrero, Virginia, Bien, Stephanie A., Dimou, Niki, Albanes, Demetrius, Baurley, James W., Wu, Anna H., Buchanan, Daniel D., Potter, John D., Prentice, Ross L., Harlid, Sophia, Arndt, Volker, Barry, Elizabeth L., Berndt, Sonja I., Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chang-Claude, Jenny, Conti, David V., Devall, Matthew A M, Figueiredo, Jane C., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kundaje, Anshul, Le Marchand, Loic, Li, Li, Lynch, Brigid M., Murphy, Neil, Nassir, Rami, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Stern, Mariana C., Su, Yu-Ru, Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, White, Emily, Hsu, Li, Moreno, Victor, Peters, Ulrike, Chan, Andrew T., and Gauderman, W James
Abstract: Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
Published: 2024
Full Text: View/download PDF

3. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk

Author: Tian, Yu, Lin, Yi, Qu, Conghui, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chan, Andrew T., Chen, Rui, Chen, Xuechen, Conti, David V., Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harlid, Sophia, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Joshi, Amit D., Keku, Temitope O., Kawaguchi, Eric, Kim, Andre E., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Moreno, Victor, Morrison, John, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward A., Sakoda, Lori C., Schoen, Robert E., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Thibodeau, Stephen N., Thomas, Duncan C., Tsilidis, Konstantinos K., van Duijnhoven, Franzel J. B., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Peters, Ulrike, Gauderman, W. James, Hsu, Li, Chang-Claude, Jenny, Tian, Yu, Lin, Yi, Qu, Conghui, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chan, Andrew T., Chen, Rui, Chen, Xuechen, Conti, David V., Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harlid, Sophia, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Joshi, Amit D., Keku, Temitope O., Kawaguchi, Eric, Kim, Andre E., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Moreno, Victor, Morrison, John, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward A., Sakoda, Lori C., Schoen, Robert E., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Thibodeau, Stephen N., Thomas, Duncan C., Tsilidis, Konstantinos K., van Duijnhoven, Franzel J. B., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Peters, Ulrike, Gauderman, W. James, Hsu, Li, and Chang-Claude, Jenny
Abstract: Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10−8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%–4.0%) vs 6.1% (5.7%–6.5%) (difference 2.4%, P-value = 1.83 × 10−14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%–1.8%) vs 2.2% (1.9%–2.4%) (difference 0.6%, P-value = 1.01 × 10−3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
Published: 2024
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4. 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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5. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk

Author: Tian, Yu, Lin, Yi, Qu, Conghui, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chan, Andrew T., Chen, Rui, Chen, Xuechen, Conti, David V., Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harlid, Sophia, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Joshi, Amit D., Keku, Temitope O., Kawaguchi, Eric, Kim, Andre E., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Moreno, Victor, Morrison, John, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward A., Sakoda, Lori C., Schoen, Robert E., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Thibodeau, Stephen N., Thomas, Duncan C., Tsilidis, Konstantinos K., van Duijnhoven, Franzel J. B., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Peters, Ulrike, Gauderman, W. James, Hsu, Li, Chang-Claude, Jenny, Tian, Yu, Lin, Yi, Qu, Conghui, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chan, Andrew T., Chen, Rui, Chen, Xuechen, Conti, David V., Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harlid, Sophia, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Joshi, Amit D., Keku, Temitope O., Kawaguchi, Eric, Kim, Andre E., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Moreno, Victor, Morrison, John, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward A., Sakoda, Lori C., Schoen, Robert E., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Thibodeau, Stephen N., Thomas, Duncan C., Tsilidis, Konstantinos K., van Duijnhoven, Franzel J. B., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Peters, Ulrike, Gauderman, W. James, Hsu, Li, and Chang-Claude, Jenny
Abstract: Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10−8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%–4.0%) vs 6.1% (5.7%–6.5%) (difference 2.4%, P-value = 1.83 × 10−14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%–1.8%) vs 2.2% (1.9%–2.4%) (difference 0.6%, P-value = 1.01 × 10−3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
Published: 2024
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6. Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer

Author: Drew, David A., Kim, Andre E., Lin, Yi, Qu, Conghui, Morrison, John, Lewinger, Juan Pablo, Kawaguchi, Eric, Wang, Jun, Fu, Yubo, Zemlianskaia, Natalia, Díez-Obrero, Virginia, Bien, Stephanie A., Dimou, Niki, Albanes, Demetrius, Baurley, James W., Wu, Anna H., Buchanan, Daniel D., Potter, John D., Prentice, Ross L., Harlid, Sophia, Arndt, Volker, Barry, Elizabeth L., Berndt, Sonja I., Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chang-Claude, Jenny, Conti, David V., Devall, Matthew A M, Figueiredo, Jane C., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kundaje, Anshul, Le Marchand, Loic, Li, Li, Lynch, Brigid M., Murphy, Neil, Nassir, Rami, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Stern, Mariana C., Su, Yu-Ru, Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, White, Emily, Hsu, Li, Moreno, Victor, Peters, Ulrike, Chan, Andrew T., Gauderman, W James, Drew, David A., Kim, Andre E., Lin, Yi, Qu, Conghui, Morrison, John, Lewinger, Juan Pablo, Kawaguchi, Eric, Wang, Jun, Fu, Yubo, Zemlianskaia, Natalia, Díez-Obrero, Virginia, Bien, Stephanie A., Dimou, Niki, Albanes, Demetrius, Baurley, James W., Wu, Anna H., Buchanan, Daniel D., Potter, John D., Prentice, Ross L., Harlid, Sophia, Arndt, Volker, Barry, Elizabeth L., Berndt, Sonja I., Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chang-Claude, Jenny, Conti, David V., Devall, Matthew A M, Figueiredo, Jane C., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kundaje, Anshul, Le Marchand, Loic, Li, Li, Lynch, Brigid M., Murphy, Neil, Nassir, Rami, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Stern, Mariana C., Su, Yu-Ru, Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, White, Emily, Hsu, Li, Moreno, Victor, Peters, Ulrike, Chan, Andrew T., and Gauderman, W James
Abstract: Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
Published: 2024
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7. 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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8. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author: Bradfield, Jonathan P., Kember, Rachel L., Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M., Bell, Joshua A., Broadaway, K. Alaine, Chen, Zhanghua, Chai, Jin Fang, Davies, Neil M., Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M., Have, Christian Theil, Strachan, David P., Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H., Wang, Carol A., Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W. James, Glessner, Joseph T., Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L., Guxens, Mònica, Felix, Janine F., Hansen, Torben, Jaddoe, Vincent W.V., Perry, John R.B., Rivadeneira, Fernando, Bradfield, Jonathan P., Kember, Rachel L., Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M., Bell, Joshua A., Broadaway, K. Alaine, Chen, Zhanghua, Chai, Jin Fang, Davies, Neil M., Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M., Have, Christian Theil, Strachan, David P., Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H., Wang, Carol A., Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W. James, Glessner, Joseph T., Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L., Guxens, Mònica, Felix, Janine F., Hansen, Torben, Jaddoe, Vincent W.V., Perry, John R.B., and Rivadeneira, Fernando
Abstract: BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.
Published: 2024

9. Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer

Author: Drew, David A., Kim, Andre E., Lin, Yi, Qu, Conghui, Morrison, John, Lewinger, Juan Pablo, Kawaguchi, Eric, Wang, Jun, Fu, Yubo, Zemlianskaia, Natalia, Díez-Obrero, Virginia, Bien, Stephanie A., Dimou, Niki, Albanes, Demetrius, Baurley, James W., Wu, Anna H., Buchanan, Daniel D., Potter, John D., Prentice, Ross L., Harlid, Sophia, Arndt, Volker, Barry, Elizabeth L., Berndt, Sonja I., Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chang-Claude, Jenny, Conti, David V., Devall, Matthew A M, Figueiredo, Jane C., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kundaje, Anshul, Le Marchand, Loic, Li, Li, Lynch, Brigid M., Murphy, Neil, Nassir, Rami, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Stern, Mariana C., Su, Yu-Ru, Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, White, Emily, Hsu, Li, Moreno, Victor, Peters, Ulrike, Chan, Andrew T., Gauderman, W James, Drew, David A., Kim, Andre E., Lin, Yi, Qu, Conghui, Morrison, John, Lewinger, Juan Pablo, Kawaguchi, Eric, Wang, Jun, Fu, Yubo, Zemlianskaia, Natalia, Díez-Obrero, Virginia, Bien, Stephanie A., Dimou, Niki, Albanes, Demetrius, Baurley, James W., Wu, Anna H., Buchanan, Daniel D., Potter, John D., Prentice, Ross L., Harlid, Sophia, Arndt, Volker, Barry, Elizabeth L., Berndt, Sonja I., Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chang-Claude, Jenny, Conti, David V., Devall, Matthew A M, Figueiredo, Jane C., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kundaje, Anshul, Le Marchand, Loic, Li, Li, Lynch, Brigid M., Murphy, Neil, Nassir, Rami, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Stern, Mariana C., Su, Yu-Ru, Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, White, Emily, Hsu, Li, Moreno, Victor, Peters, Ulrike, Chan, Andrew T., and Gauderman, W James
Abstract: Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
Published: 2024
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10. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk

Author: Tian, Yu, Lin, Yi, Qu, Conghui, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chan, Andrew T., Chen, Rui, Chen, Xuechen, Conti, David V., Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harlid, Sophia, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Joshi, Amit D., Keku, Temitope O., Kawaguchi, Eric, Kim, Andre E., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Moreno, Victor, Morrison, John, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward A., Sakoda, Lori C., Schoen, Robert E., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Thibodeau, Stephen N., Thomas, Duncan C., Tsilidis, Konstantinos K., van Duijnhoven, Franzel J. B., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Peters, Ulrike, Gauderman, W. James, Hsu, Li, Chang-Claude, Jenny, Tian, Yu, Lin, Yi, Qu, Conghui, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chan, Andrew T., Chen, Rui, Chen, Xuechen, Conti, David V., Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harlid, Sophia, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Joshi, Amit D., Keku, Temitope O., Kawaguchi, Eric, Kim, Andre E., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Moreno, Victor, Morrison, John, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward A., Sakoda, Lori C., Schoen, Robert E., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Thibodeau, Stephen N., Thomas, Duncan C., Tsilidis, Konstantinos K., van Duijnhoven, Franzel J. B., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Peters, Ulrike, Gauderman, W. James, Hsu, Li, and Chang-Claude, Jenny
Abstract: Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10−8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%–4.0%) vs 6.1% (5.7%–6.5%) (difference 2.4%, P-value = 1.83 × 10−14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%–1.8%) vs 2.2% (1.9%–2.4%) (difference 0.6%, P-value = 1.01 × 10−3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
Published: 2024
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11. 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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12. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author: Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, Cousminer, Diana L, Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, and Cousminer, Diana L
Abstract: Background: Pubertal growth patterns correlate with future health outcomes. How‑ever, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Transla‑tion And Rotation (SITAR) growth curve analysis on~56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analy‑ses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results: Large-scale growth modeling enables an unprecedented view of adoles‑ cent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide signifcant loci and leverage trans-ancestry data to perform fnemapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with diferent growth trajectories correlated with dif‑ferent outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fbrillation. Conclusion: We report novel genetic associations with the tempo of pubertal growth and fnd that genetic determinants of growth are correlated with reproductive, glyce‑mic, respiratory, and cardiac traits in adulthood. These results aid in identifying specifc growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern., BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation.CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.
Published: 2024

13. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author: Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, Cousminer, Diana L, Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, and Cousminer, Diana L
Abstract: Background: Pubertal growth patterns correlate with future health outcomes. How‑ever, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Transla‑tion And Rotation (SITAR) growth curve analysis on~56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analy‑ses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results: Large-scale growth modeling enables an unprecedented view of adoles‑ cent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide signifcant loci and leverage trans-ancestry data to perform fnemapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with diferent growth trajectories correlated with dif‑ferent outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fbrillation. Conclusion: We report novel genetic associations with the tempo of pubertal growth and fnd that genetic determinants of growth are correlated with reproductive, glyce‑mic, respiratory, and cardiac traits in adulthood. These results aid in identifying specifc growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern., BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation.CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.
Published: 2024

14. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk

Author: Tian, Yu, Lin, Yi, Qu, Conghui, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chan, Andrew T., Chen, Rui, Chen, Xuechen, Conti, David V., Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harlid, Sophia, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Joshi, Amit D., Keku, Temitope O., Kawaguchi, Eric, Kim, Andre E., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Moreno, Victor, Morrison, John, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward A., Sakoda, Lori C., Schoen, Robert E., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Thibodeau, Stephen N., Thomas, Duncan C., Tsilidis, Konstantinos K., van Duijnhoven, Franzel J. B., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Peters, Ulrike, Gauderman, W. James, Hsu, Li, Chang-Claude, Jenny, Tian, Yu, Lin, Yi, Qu, Conghui, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Chan, Andrew T., Chen, Rui, Chen, Xuechen, Conti, David V., Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harlid, Sophia, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Joshi, Amit D., Keku, Temitope O., Kawaguchi, Eric, Kim, Andre E., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Moreno, Victor, Morrison, John, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward A., Sakoda, Lori C., Schoen, Robert E., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Thibodeau, Stephen N., Thomas, Duncan C., Tsilidis, Konstantinos K., van Duijnhoven, Franzel J. B., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Peters, Ulrike, Gauderman, W. James, Hsu, Li, and Chang-Claude, Jenny
Abstract: Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10−8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%–4.0%) vs 6.1% (5.7%–6.5%) (difference 2.4%, P-value = 1.83 × 10−14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%–1.8%) vs 2.2% (1.9%–2.4%) (difference 0.6%, P-value = 1.01 × 10−3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
Published: 2024
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15. Genome-wide interaction analysis of folate for colorectal cancer risk

Author: Bouras, Emmanouil, Kim, Andre E., Lin, Yi, Morrison, John, Du, Mengmeng, Albanes, Demetrius, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, Timothy D., Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Conti, David V., Cotterchio, Michelle, Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Männistö, Satu, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Obón-Santacana, Mireia, Ose, Jennifer, Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Qi, Lihong, Qu, Conghui, Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Schmit, Stephanie L., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Um, Caroline Y., van Duijnhoven, Franzel JB., van Guelpen, Bethany, Visvanathan, Kala, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Ulrich, Cornelia M., Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., Bouras, Emmanouil, Kim, Andre E., Lin, Yi, Morrison, John, Du, Mengmeng, Albanes, Demetrius, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, Timothy D., Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Conti, David V., Cotterchio, Michelle, Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Männistö, Satu, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Obón-Santacana, Mireia, Ose, Jennifer, Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Qi, Lihong, Qu, Conghui, Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Schmit, Stephanie L., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Um, Caroline Y., van Duijnhoven, Franzel JB., van Guelpen, Bethany, Visvanathan, Kala, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Ulrich, Cornelia M., Hsu, Li, Gauderman, W James, Peters, Ulrike, and Tsilidis, Konstantinos K.
Abstract: Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. Conclusions: Variation in 3p25.2 locus may modify the
Published: 2023
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16. Genome-wide interaction analysis of folate for colorectal cancer risk

Author: Bouras, Emmanouil, Kim, Andre E., Lin, Yi, Morrison, John, Du, Mengmeng, Albanes, Demetrius, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, Timothy D., Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Conti, David V., Cotterchio, Michelle, Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Männistö, Satu, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Obón-Santacana, Mireia, Ose, Jennifer, Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Qi, Lihong, Qu, Conghui, Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Schmit, Stephanie L., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Um, Caroline Y., van Duijnhoven, Franzel JB., van Guelpen, Bethany, Visvanathan, Kala, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Ulrich, Cornelia M., Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., Bouras, Emmanouil, Kim, Andre E., Lin, Yi, Morrison, John, Du, Mengmeng, Albanes, Demetrius, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, Timothy D., Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Conti, David V., Cotterchio, Michelle, Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Männistö, Satu, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Obón-Santacana, Mireia, Ose, Jennifer, Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Qi, Lihong, Qu, Conghui, Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Schmit, Stephanie L., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Um, Caroline Y., van Duijnhoven, Franzel JB., van Guelpen, Bethany, Visvanathan, Kala, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Ulrich, Cornelia M., Hsu, Li, Gauderman, W James, Peters, Ulrike, and Tsilidis, Konstantinos K.
Abstract: Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. Conclusions: Variation in 3p25.2 locus may modify the
Published: 2023
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17. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author: Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., Tobin, Martin, Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin
Abstract: Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Published: 2023
Full Text: View/download PDF

18. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author: Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., Tobin, Martin, Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin
Abstract: Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Published: 2023
Full Text: View/download PDF

19. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author: Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., Tobin, Martin, Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin
Abstract: Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Published: 2023
Full Text: View/download PDF

20. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author: Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., Campbell, Peter T., Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., and Campbell, Peter T.
Abstract: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Published: 2023
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21. The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.

Author: Weinstock, Joshua S, Weinstock, Joshua S, Laurie, Cecelia A, Broome, Jai G, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O'Connell, Jeffrey R, Lewis, Joshua P, Boerwinkle, Eric, Barnes, Kathleen C, Chami, Nathalie, Kenny, Eimear E, Loos, Ruth JF, Fornage, Myriam, Redline, Susan, Cade, Brian E, Gilliland, Frank D, Chen, Zhanghua, Gauderman, W James, Kumar, Rajesh, Grammer, Leslie, Schleimer, Robert P, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Qiao, Dandi, Weiss, Scott T, Lasky-Su, Jessica, DeMeo, Dawn L, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Cho, Michael H, Vasan, Ramachandran S, Johnson, Andrew D, Yanek, Lisa R, Becker, Lewis C, Kardia, Sharon, He, Jiang, Kaplan, Robert, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Arnett, Donna K, Irvin, Marguerite R, Tiwari, Hemant, Correa, Adolfo, Raffield, Laura M, Gao, Yan, de Andrade, Mariza, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Konkle, Barbara A, Johnsen, Jill M, Wheeler, Marsha M, Custer, Brian S, Duggirala, Ravindranath, Curran, Joanne E, Blangero, John, Gui, Hongsheng, Xiao, Shujie, Williams, L Keoki, Meyers, Deborah A, Li, Xingnan, Ortega, Victor, McGarvey, Stephen, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Desai, Pinkal, Blackwell, Thomas W, Abecasis, Goncalo R, Smith, Albert V, Kang, Hyun M, Mathias, Rasika, Natarajan, Pradeep, Jaiswal, Siddhartha, Reiner, Alexander P, Bick, Alexander G, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Weinstock, Joshua S, Weinstock, Joshua S, Laurie, Cecelia A, Broome, Jai G, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O'Connell, Jeffrey R, Lewis, Joshua P, Boerwinkle, Eric, Barnes, Kathleen C, Chami, Nathalie, Kenny, Eimear E, Loos, Ruth JF, Fornage, Myriam, Redline, Susan, Cade, Brian E, Gilliland, Frank D, Chen, Zhanghua, Gauderman, W James, Kumar, Rajesh, Grammer, Leslie, Schleimer, Robert P, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Qiao, Dandi, Weiss, Scott T, Lasky-Su, Jessica, DeMeo, Dawn L, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Cho, Michael H, Vasan, Ramachandran S, Johnson, Andrew D, Yanek, Lisa R, Becker, Lewis C, Kardia, Sharon, He, Jiang, Kaplan, Robert, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Arnett, Donna K, Irvin, Marguerite R, Tiwari, Hemant, Correa, Adolfo, Raffield, Laura M, Gao, Yan, de Andrade, Mariza, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Konkle, Barbara A, Johnsen, Jill M, Wheeler, Marsha M, Custer, Brian S, Duggirala, Ravindranath, Curran, Joanne E, Blangero, John, Gui, Hongsheng, Xiao, Shujie, Williams, L Keoki, Meyers, Deborah A, Li, Xingnan, Ortega, Victor, McGarvey, Stephen, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Desai, Pinkal, Blackwell, Thomas W, Abecasis, Goncalo R, Smith, Albert V, Kang, Hyun M, Mathias, Rasika, Natarajan, Pradeep, Jaiswal, Siddhartha, Reiner, Alexander P, Bick, Alexander G, and NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Abstract: Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.
Published: 2023

22. Genome-wide interaction study with smoking for colorectal cancer risk identifies novel genetic loci related to tumor suppression, inflammation, and immune response

Author: Carreras-Torres, Robert, Kim, Andre E., Lin, Yi, Díez-Obrero, Virginia, Bien, Stephanie A., Qu, Conghui, Wang, Jun, Dimou, Niki, Aglago, Elom K., Albanes, Demetrius, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bézieau, Stéphane, Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Campbell, Peter T., Casey, Graham, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Dampier, Christopher H., Devall, Matthew A M, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kawaguchi, Eric, Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Mahesworo, Bharuno, Morrison, John L., Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Pharoah, Paul D P, Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Cenggoro, Tjeng Wawan, Weinstein, Stephanie J., White, Emily, Wolk, Alicja, Woods, Michael O., Hsu, Li, Peters, Ulrike, Moreno, Victor, Gauderman, W. James, Carreras-Torres, Robert, Kim, Andre E., Lin, Yi, Díez-Obrero, Virginia, Bien, Stephanie A., Qu, Conghui, Wang, Jun, Dimou, Niki, Aglago, Elom K., Albanes, Demetrius, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bézieau, Stéphane, Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Budiarto, Arif, Campbell, Peter T., Casey, Graham, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Dampier, Christopher H., Devall, Matthew A M, Drew, David A., Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina M., Kawaguchi, Eric, Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Mahesworo, Bharuno, Morrison, John L., Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Obón-Santacana, Mireia, Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Pharoah, Paul D P, Platz, Elizabeth A., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Tsilidis, Konstantinos K., Ulrich, Cornelia M., van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Cenggoro, Tjeng Wawan, Weinstein, Stephanie J., White, Emily, Wolk, Alicja, Woods, Michael O., Hsu, Li, Peters, Ulrike, Moreno, Victor, and Gauderman, W. James
Abstract: BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. IMPACT: These findings can guide potential prevention treatments.
Published: 2023
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23. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author: Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., Campbell, Peter T., Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., and Campbell, Peter T.
Abstract: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Published: 2023
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24. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author: Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., Tobin, Martin, Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin
Abstract: Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Published: 2023
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25. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author: Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., Campbell, Peter T., Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., and Campbell, Peter T.
Abstract: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Published: 2023
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26. Gene-environment analyses reveal novel genetic candidates with prenatal tobacco exposure in relation to risk for childhood acute lymphoblastic leukemia.

Author: Zhong, Charlie, Zhong, Charlie, Li, Shaobo, Arroyo, Katti, Morimoto, Libby M, de Smith, Adam J, Metayer, Catherine, Ma, Xiaomei, Kogan, Scott C, Gauderman, W James, Wiemels, Joseph L, Zhong, Charlie, Zhong, Charlie, Li, Shaobo, Arroyo, Katti, Morimoto, Libby M, de Smith, Adam J, Metayer, Catherine, Ma, Xiaomei, Kogan, Scott C, Gauderman, W James, and Wiemels, Joseph L
Abstract: BackgroundAssociations between maternal tobacco exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have yielded mixed results. This may be due to biases in self-reported smoking or other differences in individual level risk factors. We utilized a biological marker of maternal tobacco exposure to evaluate the association between maternal tobacco exposure during pregnancy, genetics, and subsequent childhood ALL risk in two large population-based studies of childhood ALL in California.MethodsMaternal exposure to tobacco smoke was assessed with a validated methylation marker (cg05575921) of the aryl hydrocarbon receptor repressor (AHRR) gene in newborn dried blood spots. We adjusted for sex, birthweight, gestational age, mode of delivery, year of birth, AHRR quantitative trait locus (mQTL) rs77111113, and a polygenetic risk score for childhood ALL. We additionally adjusted for principal components in a gene-environment interaction testing method that incorporates gene-only and environment-only effects along with interactions.ResultsAHRR hypomethylation overall was not associated with childhood ALL. In gene-environment interaction testing, several genetic variants displayed significant interaction with AHRR hypomethylation and childhood ALL.ConclusionsOur results suggest novel candidates in PTPRK and DPP6 may play a role in tobacco-related leukemogenesis. Further research is necessary to better understand the effects of tobacco and these variants on childhood ALL risk.ImpactDespite lack of an overall "main effect," tobacco exposure during pregnancy impacts childhood ALL risk depending on specific genetic variants.
Published: 2023

27. Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure

Author: Guirette, Mélanie, Lan, Jessie, McKeown, Nicola, Brown, Michael R, Chen, Han, DE Vries, Paul S, Kim, Hyunju, Rebholz, Casey M, Morrison, Alanna C, Bartz, Traci M, Fretts, Amanda M, Guo, Xiuqing, Lemaitre, Rozenn N, Liu, Ching-Ti, Noordam, Raymond, DE Mutsert, Renée, Rosendaal, Frits R, Wang, Carol A, Beilin, Lawrence, Mori, Trevor A, Oddy, Wendy H, Pennell, Craig E, Chai, Jin Fang, Whitton, Clare, VAN Dam, Rob M, Liu, Jianjun, Tai, E Shyong, Sim, Xueling, Neuhouser, Marian L, Kooperberg, Charles, Tinker, Lesley, Franceschini, Nora, Huan, Tianxiao, Winkler, Thomas W, Bentley, Amy R, Gauderman, W James, Heerkens, Luc, Tanaka, Toshiko, van Rooij, Jeroen, Munroe, Patricia B, Warren, Helen R, Voortman, Trudy, Chen, Honglei, Rao, D C, Levy, Daniel, Ma, Jiantao, Guirette, Mélanie, Lan, Jessie, McKeown, Nicola, Brown, Michael R, Chen, Han, DE Vries, Paul S, Kim, Hyunju, Rebholz, Casey M, Morrison, Alanna C, Bartz, Traci M, Fretts, Amanda M, Guo, Xiuqing, Lemaitre, Rozenn N, Liu, Ching-Ti, Noordam, Raymond, DE Mutsert, Renée, Rosendaal, Frits R, Wang, Carol A, Beilin, Lawrence, Mori, Trevor A, Oddy, Wendy H, Pennell, Craig E, Chai, Jin Fang, Whitton, Clare, VAN Dam, Rob M, Liu, Jianjun, Tai, E Shyong, Sim, Xueling, Neuhouser, Marian L, Kooperberg, Charles, Tinker, Lesley, Franceschini, Nora, Huan, Tianxiao, Winkler, Thomas W, Bentley, Amy R, Gauderman, W James, Heerkens, Luc, Tanaka, Toshiko, van Rooij, Jeroen, Munroe, Patricia B, Warren, Helen R, Voortman, Trudy, Chen, Honglei, Rao, D C, Levy, Daniel, and Ma, Jiantao
Abstract: OBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.
Published: 2023

28. Genome-wide interaction analysis of folate for colorectal cancer risk

Author: Bouras, Emmanouil, Kim, Andre E., Lin, Yi, Morrison, John, Du, Mengmeng, Albanes, Demetrius, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, Timothy D., Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Conti, David V., Cotterchio, Michelle, Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Männistö, Satu, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Obón-Santacana, Mireia, Ose, Jennifer, Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Qi, Lihong, Qu, Conghui, Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Schmit, Stephanie L., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Um, Caroline Y., van Duijnhoven, Franzel JB., van Guelpen, Bethany, Visvanathan, Kala, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Ulrich, Cornelia M., Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., Bouras, Emmanouil, Kim, Andre E., Lin, Yi, Morrison, John, Du, Mengmeng, Albanes, Demetrius, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, Timothy D., Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Conti, David V., Cotterchio, Michelle, Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Männistö, Satu, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Obón-Santacana, Mireia, Ose, Jennifer, Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Qi, Lihong, Qu, Conghui, Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Schmit, Stephanie L., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Um, Caroline Y., van Duijnhoven, Franzel JB., van Guelpen, Bethany, Visvanathan, Kala, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Ulrich, Cornelia M., Hsu, Li, Gauderman, W James, Peters, Ulrike, and Tsilidis, Konstantinos K.
Abstract: Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. Conclusions: Variation in 3p25.2 locus may modify the
Published: 2023
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29. Genome-wide interaction analysis of folate for colorectal cancer risk

Author: Bouras, Emmanouil, Kim, Andre E., Lin, Yi, Morrison, John, Du, Mengmeng, Albanes, Demetrius, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, Timothy D., Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Conti, David V., Cotterchio, Michelle, Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Männistö, Satu, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Obón-Santacana, Mireia, Ose, Jennifer, Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Qi, Lihong, Qu, Conghui, Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Schmit, Stephanie L., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Um, Caroline Y., van Duijnhoven, Franzel JB., van Guelpen, Bethany, Visvanathan, Kala, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Ulrich, Cornelia M., Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., Bouras, Emmanouil, Kim, Andre E., Lin, Yi, Morrison, John, Du, Mengmeng, Albanes, Demetrius, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, Timothy D., Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter T., Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Conti, David V., Cotterchio, Michelle, Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gruber, Stephen B., Gunter, Marc J., Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Männistö, Satu, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Obón-Santacana, Mireia, Ose, Jennifer, Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew J., Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Qi, Lihong, Qu, Conghui, Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Schmit, Stephanie L., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thomas, Duncan C., Tian, Yu, Um, Caroline Y., van Duijnhoven, Franzel JB., van Guelpen, Bethany, Visvanathan, Kala, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Ulrich, Cornelia M., Hsu, Li, Gauderman, W James, Peters, Ulrike, and Tsilidis, Konstantinos K.
Abstract: Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. Conclusions: Variation in 3p25.2 locus may modify the
Published: 2023
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30. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author: Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W. James, Peters, Ulrike, Tsilidis, Konstantinos K., Campbell, Peter T., Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W. James, Peters, Ulrike, Tsilidis, Konstantinos K., and Campbell, Peter T.
Abstract: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Geneenvironment interactions (G E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant GBMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategie, Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Published: 2023

31. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author: Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., Tobin, Martin, Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Ismail, Said I., Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Abu Saqri, Tariq, Khatib, Mohammedhusen, Hamza, Mehshad, Abu Zaid, Tariq, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh, V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimaki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietilainen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josee, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin
Abstract: Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Published: 2023
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32. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author: Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., Campbell, Peter T., Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., and Campbell, Peter T.
Abstract: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Published: 2023
Full Text: View/download PDF

33. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author: Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., Campbell, Peter T., Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W James, Peters, Ulrike, Tsilidis, Konstantinos K., and Campbell, Peter T.
Abstract: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Published: 2023
Full Text: View/download PDF

34. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author: Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W. James, Peters, Ulrike, Tsilidis, Konstantinos K., Campbell, Peter T., Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W. James, Peters, Ulrike, Tsilidis, Konstantinos K., and Campbell, Peter T.
Abstract: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Geneenvironment interactions (G E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant GBMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategie, Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Published: 2023

35. Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

Author: Tian, Yu, Kim, Andre E, Bien, Stephanie A, Lin, Yi, Qu, Conghui, Harrison, Tabitha A, Carreras-Torres, Robert, Díez-Obrero, Virginia, Dimou, Niki, Drew, David A, Hidaka, Akihisa, Huyghe, Jeroen R, Jordahl, Kristina M, Morrison, John, Murphy, Neil, Obón-Santacana, Mireia, Ulrich, Cornelia M, Ose, Jennifer, Peoples, Anita R, Ruiz-Narvaez, Edward A, Shcherbina, Anna, Stern, Mariana C, Su, Yu-Ru, van Duijnhoven, Franzel J B, Arndt, Volker, Baurley, James W, Berndt, Sonja I, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Chan, Andrew T, Figueiredo, Jane C, Gallinger, Steven, Gruber, Stephen B, Harlid, Sophia, Hoffmeister, Michael, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Larsson, Susanna C., Le Marchand, Loic, Li, Li, Giles, Graham G, Milne, Roger L, Nan, Hongmei, Nassir, Rami, Ogino, Shuji, Budiarto, Arif, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Rennert, Gad, Sakoda, Lori C, Schoen, Robert E, Slattery, Martha L, Thibodeau, Stephen N, Van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Campbell, Peter T, Casey, Graham, Conti, David V, Gunter, Marc J, Kundaje, Anshul, Lewinger, Juan Pablo, Moreno, Victor, Newcomb, Polly A, Pardamean, Bens, Thomas, Duncan C, Tsilidis, Konstantinos K, Peters, Ulrike, Gauderman, W James, Hsu, Li, Chang-Claude, Jenny, Tian, Yu, Kim, Andre E, Bien, Stephanie A, Lin, Yi, Qu, Conghui, Harrison, Tabitha A, Carreras-Torres, Robert, Díez-Obrero, Virginia, Dimou, Niki, Drew, David A, Hidaka, Akihisa, Huyghe, Jeroen R, Jordahl, Kristina M, Morrison, John, Murphy, Neil, Obón-Santacana, Mireia, Ulrich, Cornelia M, Ose, Jennifer, Peoples, Anita R, Ruiz-Narvaez, Edward A, Shcherbina, Anna, Stern, Mariana C, Su, Yu-Ru, van Duijnhoven, Franzel J B, Arndt, Volker, Baurley, James W, Berndt, Sonja I, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Chan, Andrew T, Figueiredo, Jane C, Gallinger, Steven, Gruber, Stephen B, Harlid, Sophia, Hoffmeister, Michael, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Larsson, Susanna C., Le Marchand, Loic, Li, Li, Giles, Graham G, Milne, Roger L, Nan, Hongmei, Nassir, Rami, Ogino, Shuji, Budiarto, Arif, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Rennert, Gad, Sakoda, Lori C, Schoen, Robert E, Slattery, Martha L, Thibodeau, Stephen N, Van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Campbell, Peter T, Casey, Graham, Conti, David V, Gunter, Marc J, Kundaje, Anshul, Lewinger, Juan Pablo, Moreno, Victor, Newcomb, Polly A, Pardamean, Bens, Thomas, Duncan C, Tsilidis, Konstantinos K, Peters, Ulrike, Gauderman, W James, Hsu, Li, and Chang-Claude, Jenny
Abstract: BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
Published: 2022
Full Text: View/download PDF

36. Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

Author: Tian, Yu, Kim, Andre E., Bien, Stephanie A., Lin, Yi, Qu, Conghui, Harrison, Tabitha A., Carreras-Torres, Robert, Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Hidaka, Akihisa, Huyghe, Jeroen R., Jordahl, Kristina M., Morrison, John, Murphy, Neil, Obón-Santacana, Mireia, Ulrich, Cornelia M., Ose, Jennifer, Peoples, Anita R., Ruiz-Narvaez, Edward A., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, van Duijnhoven, Franzel J B, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D., Chan, Andrew T., Figueiredo, Jane C., Gallinger, Steven, Gruber, Stephen B., Harlid, Sophia, Hoffmeister, Michael, Jenkins, Mark A., Joshi, Amit D., Keku, Temitope O., Larsson, Susanna C., Le Marchand, Loic, Li, Li, Giles, Graham G., Milne, Roger L., Nan, Hongmei, Nassir, Rami, Ogino, Shuji, Budiarto, Arif, Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Sakoda, Lori C., Schoen, Robert E., Slattery, Martha L., Thibodeau, Stephen N., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Campbell, Peter T., Casey, Graham, Conti, David V., Gunter, Marc J., Kundaje, Anshul, Lewinger, Juan Pablo, Moreno, Victor, Newcomb, Polly A., Pardamean, Bens, Thomas, Duncan C., Tsilidis, Konstantinos K., Peters, Ulrike, Gauderman, W James, Hsu, Li, Chang-Claude, Jenny, Tian, Yu, Kim, Andre E., Bien, Stephanie A., Lin, Yi, Qu, Conghui, Harrison, Tabitha A., Carreras-Torres, Robert, Díez-Obrero, Virginia, Dimou, Niki, Drew, David A., Hidaka, Akihisa, Huyghe, Jeroen R., Jordahl, Kristina M., Morrison, John, Murphy, Neil, Obón-Santacana, Mireia, Ulrich, Cornelia M., Ose, Jennifer, Peoples, Anita R., Ruiz-Narvaez, Edward A., Shcherbina, Anna, Stern, Mariana C., Su, Yu-Ru, van Duijnhoven, Franzel J B, Arndt, Volker, Baurley, James W., Berndt, Sonja I., Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D., Chan, Andrew T., Figueiredo, Jane C., Gallinger, Steven, Gruber, Stephen B., Harlid, Sophia, Hoffmeister, Michael, Jenkins, Mark A., Joshi, Amit D., Keku, Temitope O., Larsson, Susanna C., Le Marchand, Loic, Li, Li, Giles, Graham G., Milne, Roger L., Nan, Hongmei, Nassir, Rami, Ogino, Shuji, Budiarto, Arif, Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Sakoda, Lori C., Schoen, Robert E., Slattery, Martha L., Thibodeau, Stephen N., van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Campbell, Peter T., Casey, Graham, Conti, David V., Gunter, Marc J., Kundaje, Anshul, Lewinger, Juan Pablo, Moreno, Victor, Newcomb, Polly A., Pardamean, Bens, Thomas, Duncan C., Tsilidis, Konstantinos K., Peters, Ulrike, Gauderman, W James, Hsu, Li, and Chang-Claude, Jenny
Abstract: BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
Published: 2022
Full Text: View/download PDF

37. Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk.

Author: Tian, Yu, Tian, Yu, Kim, Andre E, Bien, Stephanie A, Lin, Yi, Qu, Conghui, Harrison, Tabitha A, Carreras-Torres, Robert, Díez-Obrero, Virginia, Dimou, Niki, Drew, David A, Hidaka, Akihisa, Huyghe, Jeroen R, Jordahl, Kristina M, Morrison, John, Murphy, Neil, Obón-Santacana, Mireia, Ulrich, Cornelia M, Ose, Jennifer, Peoples, Anita R, Ruiz-Narvaez, Edward A, Shcherbina, Anna, Stern, Mariana C, Su, Yu-Ru, van Duijnhoven, Franzel JB, Arndt, Volker, Baurley, James W, Berndt, Sonja I, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Chan, Andrew T, Figueiredo, Jane C, Gallinger, Steven, Gruber, Stephen B, Harlid, Sophia, Hoffmeister, Michael, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Larsson, Susanna C, Le Marchand, Loic, Li, Li, Giles, Graham G, Milne, Roger L, Nan, Hongmei, Nassir, Rami, Ogino, Shuji, Budiarto, Arif, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Rennert, Gad, Sakoda, Lori C, Schoen, Robert E, Slattery, Martha L, Thibodeau, Stephen N, Van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Campbell, Peter T, Casey, Graham, Conti, David V, Gunter, Marc J, Kundaje, Anshul, Lewinger, Juan Pablo, Moreno, Victor, Newcomb, Polly A, Pardamean, Bens, Thomas, Duncan C, Tsilidis, Konstantinos K, Peters, Ulrike, Gauderman, W James, Hsu, Li, Chang-Claude, Jenny, Tian, Yu, Tian, Yu, Kim, Andre E, Bien, Stephanie A, Lin, Yi, Qu, Conghui, Harrison, Tabitha A, Carreras-Torres, Robert, Díez-Obrero, Virginia, Dimou, Niki, Drew, David A, Hidaka, Akihisa, Huyghe, Jeroen R, Jordahl, Kristina M, Morrison, John, Murphy, Neil, Obón-Santacana, Mireia, Ulrich, Cornelia M, Ose, Jennifer, Peoples, Anita R, Ruiz-Narvaez, Edward A, Shcherbina, Anna, Stern, Mariana C, Su, Yu-Ru, van Duijnhoven, Franzel JB, Arndt, Volker, Baurley, James W, Berndt, Sonja I, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Chan, Andrew T, Figueiredo, Jane C, Gallinger, Steven, Gruber, Stephen B, Harlid, Sophia, Hoffmeister, Michael, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Larsson, Susanna C, Le Marchand, Loic, Li, Li, Giles, Graham G, Milne, Roger L, Nan, Hongmei, Nassir, Rami, Ogino, Shuji, Budiarto, Arif, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Rennert, Gad, Sakoda, Lori C, Schoen, Robert E, Slattery, Martha L, Thibodeau, Stephen N, Van Guelpen, Bethany, Visvanathan, Kala, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Campbell, Peter T, Casey, Graham, Conti, David V, Gunter, Marc J, Kundaje, Anshul, Lewinger, Juan Pablo, Moreno, Victor, Newcomb, Polly A, Pardamean, Bens, Thomas, Duncan C, Tsilidis, Konstantinos K, Peters, Ulrike, Gauderman, W James, Hsu, Li, and Chang-Claude, Jenny
Abstract: BackgroundThe use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.MethodsWe conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants.ResultsThe use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4).ConclusionGenetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
Published: 2022

38. Increased burden of familial-associated early-onset cancer risk among minority Americans compared to non-Latino Whites.

Author: Feng, Qianxi, Feng, Qianxi, Nickels, Eric, Muskens, Ivo S, de Smith, Adam J, Gauderman, W James, Yee, Amy C, Ricker, Charite, Mack, Thomas, Leavitt, Andrew D, Godley, Lucy A, Wiemels, Joseph L, Feng, Qianxi, Feng, Qianxi, Nickels, Eric, Muskens, Ivo S, de Smith, Adam J, Gauderman, W James, Yee, Amy C, Ricker, Charite, Mack, Thomas, Leavitt, Andrew D, Godley, Lucy A, and Wiemels, Joseph L
Abstract: BackgroundThe role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups.MethodsWe used linked California health registries to evaluate the relative cancer risks for first-degree relatives of patients diagnosed between ages 0 and 26, and the relative risks of developing distinct second primary malignancies (SPMs). From 1989 to 2015, we identified 29,631 cancer patients and 62,863 healthy family members. We calculated the standardized incident ratios (SIRs) of early-onset primary cancers diagnosed in proband siblings and mothers, as well as SPMs detected among early-onset patients. Analyses were stratified by self-identified race/ethnicity.ResultsGiven probands with cancer, there were increased relative risks of any cancer for siblings and mothers (SIR = 3.32; 95% confidence interval [CI]: 2.85-3.85) and of SPMs (SIR = 7.27; 95% CI: 6.56-8.03). Given a proband with solid cancer, both Latinos (SIR = 4.98; 95% CI: 3.82-6.39) and non-Latino Blacks (SIR = 7.35; 95% CI: 3.36-13.95) exhibited significantly higher relative risk of any cancer in siblings and mothers when compared to non-Latino White subjects (SIR = 3.02; 95% CI: 2.12-4.16). For hematologic cancers, higher familial risk was evident for Asian/Pacific Islanders (SIR = 7.56; 95% CI: 3.26-14.90) compared to non-Latino whites (SIR = 2.69; 95% CI: 1.62-4.20).ConclusionsThe data support a need for increased attention to the genetics of early-onset cancer predisposition and environmental factors in race/ethnic minority families in the United States.FundingThis work was supported by the V Foundation for funding this work (Grant FP067172).
Published: 2021

39. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, Peters, Ulrike, Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, and Peters, Ulrike
Abstract: Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Published: 2021
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40. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, Van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, De La Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, Peters, Ulrike, Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, Van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, De La Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, and Peters, Ulrike
Abstract: Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Published: 2021
Full Text: View/download PDF

41. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, Van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, De La Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, Peters, Ulrike, Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, Van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, De La Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, and Peters, Ulrike
Abstract: Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Published: 2021
Full Text: View/download PDF

42. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, Van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, De La Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, Peters, Ulrike, Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, Van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, De La Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, and Peters, Ulrike
Abstract: Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Published: 2021
Full Text: View/download PDF

43. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, Peters, Ulrike, Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, and Peters, Ulrike
Abstract: Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Published: 2021
Full Text: View/download PDF

44. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, Peters, Ulrike, Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, and Peters, Ulrike
Abstract: Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Published: 2021
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45. Increased burden of familial-associated early-onset cancer risk among minority Americans compared to non-Latino Whites.

Author: Feng, Qianxi, Feng, Qianxi, Nickels, Eric, Muskens, Ivo S, de Smith, Adam J, Gauderman, W James, Yee, Amy C, Ricker, Charite, Mack, Thomas, Leavitt, Andrew D, Godley, Lucy A, Wiemels, Joseph L, Feng, Qianxi, Feng, Qianxi, Nickels, Eric, Muskens, Ivo S, de Smith, Adam J, Gauderman, W James, Yee, Amy C, Ricker, Charite, Mack, Thomas, Leavitt, Andrew D, Godley, Lucy A, and Wiemels, Joseph L
Abstract: BackgroundThe role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups.MethodsWe used linked California health registries to evaluate the relative cancer risks for first-degree relatives of patients diagnosed between ages 0 and 26, and the relative risks of developing distinct second primary malignancies (SPMs). From 1989 to 2015, we identified 29,631 cancer patients and 62,863 healthy family members. We calculated the standardized incident ratios (SIRs) of early-onset primary cancers diagnosed in proband siblings and mothers, as well as SPMs detected among early-onset patients. Analyses were stratified by self-identified race/ethnicity.ResultsGiven probands with cancer, there were increased relative risks of any cancer for siblings and mothers (SIR = 3.32; 95% confidence interval [CI]: 2.85-3.85) and of SPMs (SIR = 7.27; 95% CI: 6.56-8.03). Given a proband with solid cancer, both Latinos (SIR = 4.98; 95% CI: 3.82-6.39) and non-Latino Blacks (SIR = 7.35; 95% CI: 3.36-13.95) exhibited significantly higher relative risk of any cancer in siblings and mothers when compared to non-Latino White subjects (SIR = 3.02; 95% CI: 2.12-4.16). For hematologic cancers, higher familial risk was evident for Asian/Pacific Islanders (SIR = 7.56; 95% CI: 3.26-14.90) compared to non-Latino whites (SIR = 2.69; 95% CI: 1.62-4.20).ConclusionsThe data support a need for increased attention to the genetics of early-onset cancer predisposition and environmental factors in race/ethnic minority families in the United States.FundingThis work was supported by the V Foundation for funding this work (Grant FP067172).
Published: 2021

46. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, Peters, Ulrike, Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, and Peters, Ulrike
Abstract: Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Published: 2021
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47. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Author: de las Fuentes, Lisa, Sung, Yun Ju, Noordam, Raymond, Winkler, Thomas, Feitosa, Mary F., Schwander, Karen, Bentley, Amy R., Brown, Michael R., Guo, Xiuqing, Manning, Alisa, Chasman, Daniel I., Aschard, Hugues, Bartz, Traci M., Bielak, Lawrence F., Campbell, Archie, Cheng, Ching-Yu, Dorajoo, Rajkumar, Hartwig, Fernando P., Horimoto, A.R.V.R., Li, Changwei, Li-Gao, Ruifang, Liu, Yongmei, Marten, Jonathan, Musani, Solomon K., Ntalla, Ioanna, Rankinen, Tuomo, Richard, Melissa, Sim, Xueling, Smith, Albert V., Tajuddin, Salman M., Tayo, Bamidele O., Vojinovic, Dina, Warren, Helen R., Xuan, Deng, Alver, Maris, Boissel, Mathilde, Chai, Jin-Fang, Chen, Xu, Christensen, Kaare, Divers, Jasmin, Evangelou, Evangelos, Gao, Chuan, Girotto, Giorgia, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo-Pekka, Nolte, Ilja M., Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Rueedi, Rico, Shu, Xiao-ou, Snieder, Harold, Sofer, Tamar, Takeuchi, Fumihiko, Verweij, Niek, Ware, Erin B., Weiss, Stefan, Yanek, Lisa R., Amin, Najaf, Arking, Dan E., Arnett, Donna K., Bergmann, Sven, Boerwinkle, Eric, Brody, Jennifer A., Broeckel, Ulrich, Brumat, Marco, Burke, Gregory, Cabrera, Claudia P., Canouil, Mickaël, Chee, Miao Li, Chen, Yii-Der Ida, Cocca, Massimiliano, Connell, John, de Silva, H. Janaka, de Vries, Paul S., Eiriksdottir, Gudny, Faul, Jessica D., Fisher, Virginia, Forrester, Terrence, Fox, Ervin F., Friedlander, Yechiel, Gao, He, Gigante, Bruna, Giulianini, Franco, Gu, Chi Charles, Gu, Dongfeng, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven, Ikram, M. Arfan, Irvin, Marguerite R., Kähönen, Mika, Kavousi, Maryam, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Komulainen, Pirjo, Kraja, Aldi T., Krieger, J.E., Langefeld, Carl D., Li, Yize, Liang, Jingjing, Liewald, David C. M., Liu, Ching-Ti, Liu, Jianjun, Lohman, Kurt K., Mägi, Reedik, McKenzie, Colin A., Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, Milani, Lili, Mook-Kanamori, Dennis O., Nalls, Mike A., Nelson, Christopher P., Norris, Jill M., O’Connell, Jeff, Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmer, Nicholette D., Pedersen, Nancy L., Perls, Thomas, Peters, Annette, Petersmann, Astrid, Peyser, Patricia A., Polasek, Ozren, Porteous, David J., Raffel, Leslie J., Rice, Treva K., Rotter, Jerome I., Rudan, Igor, Rueda-Ochoa, Oscar-Leonel, Sabanayagam, Charumathi, Salako, Babatunde L., Schreiner, Pamela J., Shikany, James M., Sidney, Stephen S., Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Starr, John M., Strauch, Konstantin, Swertz, Morris A., Teumer, Alexander, Tham, Yih Chung, Uitterlinden, André G., Vaidya, Dhananjay, van der Ende, M. Yldau, Waldenberger, Melanie, Wang, Lihua, Wang, Ya-Xing, Wei, Wen-Bin, Weir, David R., Wen, Wanqing, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Bowden, Donald W., Deary, Ian J., Dörr, Marcus, Esko, Tõnu, Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kammerer, Candace M., Kato, Norihiro, Lakka, Timo A., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K. E., Marques-Vidal, Pedro, Penninx, Brenda W. J. H., Samani, Nilesh J., van der Harst, Pim, Wagenknecht, Lynne E., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Bouchard, Claude, Cooper, Richard S., Correa, Adolfo, Evans, Michele K., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kelly, Tanika N., Kritchevsky, Stephen B., Levy, Daniel, Palmas, Walter R., Pereira, A.C., Province, Michael M., Psaty, Bruce M., Ridker, Paul M., Rotimi, Charles N., Tai, E. Shyong, van Dam, Rob M., van Duijn, Cornelia M., Wong, Tien Yin, Rice, Kenneth, Gauderman, W. James, Morrison, Alanna C., North, Kari E., Kardia, Sharon L. R., Caulfield, Mark J., Elliott, Paul, Munroe, Patricia B., Franks, Paul W., Rao, Dabeeru C., Fornage, Myriam, de las Fuentes, Lisa, Sung, Yun Ju, Noordam, Raymond, Winkler, Thomas, Feitosa, Mary F., Schwander, Karen, Bentley, Amy R., Brown, Michael R., Guo, Xiuqing, Manning, Alisa, Chasman, Daniel I., Aschard, Hugues, Bartz, Traci M., Bielak, Lawrence F., Campbell, Archie, Cheng, Ching-Yu, Dorajoo, Rajkumar, Hartwig, Fernando P., Horimoto, A.R.V.R., Li, Changwei, Li-Gao, Ruifang, Liu, Yongmei, Marten, Jonathan, Musani, Solomon K., Ntalla, Ioanna, Rankinen, Tuomo, Richard, Melissa, Sim, Xueling, Smith, Albert V., Tajuddin, Salman M., Tayo, Bamidele O., Vojinovic, Dina, Warren, Helen R., Xuan, Deng, Alver, Maris, Boissel, Mathilde, Chai, Jin-Fang, Chen, Xu, Christensen, Kaare, Divers, Jasmin, Evangelou, Evangelos, Gao, Chuan, Girotto, Giorgia, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo-Pekka, Nolte, Ilja M., Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Rueedi, Rico, Shu, Xiao-ou, Snieder, Harold, Sofer, Tamar, Takeuchi, Fumihiko, Verweij, Niek, Ware, Erin B., Weiss, Stefan, Yanek, Lisa R., Amin, Najaf, Arking, Dan E., Arnett, Donna K., Bergmann, Sven, Boerwinkle, Eric, Brody, Jennifer A., Broeckel, Ulrich, Brumat, Marco, Burke, Gregory, Cabrera, Claudia P., Canouil, Mickaël, Chee, Miao Li, Chen, Yii-Der Ida, Cocca, Massimiliano, Connell, John, de Silva, H. Janaka, de Vries, Paul S., Eiriksdottir, Gudny, Faul, Jessica D., Fisher, Virginia, Forrester, Terrence, Fox, Ervin F., Friedlander, Yechiel, Gao, He, Gigante, Bruna, Giulianini, Franco, Gu, Chi Charles, Gu, Dongfeng, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven, Ikram, M. Arfan, Irvin, Marguerite R., Kähönen, Mika, Kavousi, Maryam, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Komulainen, Pirjo, Kraja, Aldi T., Krieger, J.E., Langefeld, Carl D., Li, Yize, Liang, Jingjing, Liewald, David C. M., Liu, Ching-Ti, Liu, Jianjun, Lohman, Kurt K., Mägi, Reedik, McKenzie, Colin A., Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, Milani, Lili, Mook-Kanamori, Dennis O., Nalls, Mike A., Nelson, Christopher P., Norris, Jill M., O’Connell, Jeff, Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmer, Nicholette D., Pedersen, Nancy L., Perls, Thomas, Peters, Annette, Petersmann, Astrid, Peyser, Patricia A., Polasek, Ozren, Porteous, David J., Raffel, Leslie J., Rice, Treva K., Rotter, Jerome I., Rudan, Igor, Rueda-Ochoa, Oscar-Leonel, Sabanayagam, Charumathi, Salako, Babatunde L., Schreiner, Pamela J., Shikany, James M., Sidney, Stephen S., Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Starr, John M., Strauch, Konstantin, Swertz, Morris A., Teumer, Alexander, Tham, Yih Chung, Uitterlinden, André G., Vaidya, Dhananjay, van der Ende, M. Yldau, Waldenberger, Melanie, Wang, Lihua, Wang, Ya-Xing, Wei, Wen-Bin, Weir, David R., Wen, Wanqing, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Bowden, Donald W., Deary, Ian J., Dörr, Marcus, Esko, Tõnu, Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kammerer, Candace M., Kato, Norihiro, Lakka, Timo A., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K. E., Marques-Vidal, Pedro, Penninx, Brenda W. J. H., Samani, Nilesh J., van der Harst, Pim, Wagenknecht, Lynne E., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Bouchard, Claude, Cooper, Richard S., Correa, Adolfo, Evans, Michele K., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kelly, Tanika N., Kritchevsky, Stephen B., Levy, Daniel, Palmas, Walter R., Pereira, A.C., Province, Michael M., Psaty, Bruce M., Ridker, Paul M., Rotimi, Charles N., Tai, E. Shyong, van Dam, Rob M., van Duijn, Cornelia M., Wong, Tien Yin, Rice, Kenneth, Gauderman, W. James, Morrison, Alanna C., North, Kari E., Kardia, Sharon L. R., Caulfield, Mark J., Elliott, Paul, Munroe, Patricia B., Franks, Paul W., Rao, Dabeeru C., and Fornage, Myriam
Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Published: 2021
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48. Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans.

Author: Gui, Hongsheng, Gui, Hongsheng, Levin, Albert M, Hu, Donglei, Sleiman, Patrick, Xiao, Shujie, Mak, Angel CY, Yang, Mao, Barczak, Andrea J, Huntsman, Scott, Eng, Celeste, Hochstadt, Samantha, Zhang, Ellen, Whitehouse, Kyle, Simons, Samantha, Cabral, Whitney, Takriti, Sami, Abecasis, Gonçalo, Blackwell, Thomas W, Kang, Hyun Min, Nickerson, Deborah A, Germer, Soren, Lanfear, David E, Gilliland, Frank, Gauderman, W James, Kumar, Rajesh, Erle, David J, Martinez, Fernando D, Hakonarson, Hakon, Burchard, Esteban G, Williams, L Keoki, Gui, Hongsheng, Gui, Hongsheng, Levin, Albert M, Hu, Donglei, Sleiman, Patrick, Xiao, Shujie, Mak, Angel CY, Yang, Mao, Barczak, Andrea J, Huntsman, Scott, Eng, Celeste, Hochstadt, Samantha, Zhang, Ellen, Whitehouse, Kyle, Simons, Samantha, Cabral, Whitney, Takriti, Sami, Abecasis, Gonçalo, Blackwell, Thomas W, Kang, Hyun Min, Nickerson, Deborah A, Germer, Soren, Lanfear, David E, Gilliland, Frank, Gauderman, W James, Kumar, Rajesh, Erle, David J, Martinez, Fernando D, Hakonarson, Hakon, Burchard, Esteban G, and Williams, L Keoki
Abstract: Rationale: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants.Objectives: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals.Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant.Measurements and Main Results: The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.
Published: 2021

49. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, Peters, Ulrike, Huyghe, Jeroen R, Harrison, Tabitha A, Bien, Stephanie A, Hampel, Heather, Figueiredo, Jane C, Schmit, Stephanie L, Conti, David V, Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Baron, John A, Cross, Amanda J, Diergaarde, Brenda, Duggan, David, Harlid, Sophia, Imaz, Liher, Kang, Hyun Min, Levine, David M, Perduca, Vittorio, Perez-Cornago, Aurora, Sakoda, Lori C, Schumacher, Fredrick R, Slattery, Martha L, Toland, Amanda E, van Duijnhoven, Fränzel J B, Van Guelpen, Bethany, Agudo, Antonio, Albanes, Demetrius, Alonso, M Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Banbury, Barbara L, Bassik, Michael C, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Boehm, Juergen, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D, Burnett-Hartman, Andrea, Caan, Bette J, Campbell, Peter T, Carr, Prudence R, Castells, Antoni, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Curtis, Keith R, de la Chapelle, Albert, Easton, Douglas F, English, Dallas R, Feskens, Edith J M, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Goodman, Phyllis J, Grady, William M, Grove, John S, Gsur, Andrea, Gunter, Marc J, Haile, Robert W, Hampe, Jochen, Hoffmeister, Michael, Hopper, John L, Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J, Jenab, Mazda, Jenkins, Mark A, Joshi, Amit D, Keku, Temitope O, Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Christopher I, Li, Li, Lieb, Wolfgang, Lindblom, Annika, Lindor, Noralane M, Männistö, Satu, Markowitz, Sanford D, Milne, Roger L, Moreno, Lorena, Murphy, Neil, Nassir, Rami, Offit, Kenneth, Ogino, Shuji, Panico, Salvatore, Parfrey, Patrick S, Pearlman, Rachel, Pharoah, Paul D P, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Prentice, Ross L, Qi, Lihong, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Riboli, Elio, Schafmayer, Clemens, Schoen, Robert E, Seminara, Daniela, Song, Mingyang, Su, Yu-Ru, Tangen, Catherine M, Thibodeau, Stephen N, Thomas, Duncan C, Trichopoulou, Antonia, Ulrich, Cornelia M, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Abecasis, Goncalo R, Nickerson, Deborah A, Scacheri, Peter C, Kundaje, Anshul, Casey, Graham, Gruber, Stephen B, Hsu, Li, Moreno, Victor, Hayes, Richard B, Newcomb, Polly A, and Peters, Ulrike
Abstract: Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Published: 2021
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50. Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure

Author: Wang, Heming, Noordam, Raymond, Cade, Brian E, Schwander, Karen, Winkler, Thomas W, Lee, Jiwon, Sung, Yun Ju, Bentley, Amy R, Manning, Alisa K, Aschard, Hugues, Kilpeläinen, Tuomas O, Ilkov, Marjan, Brown, Michael R, Horimoto, Andrea R, Richard, Melissa, Bartz, Traci M, Vojinovic, Dina, Lim, Elise, Nierenberg, Jovia L, Liu, Yongmei, Chitrala, Kumaraswamynaidu, Rankinen, Tuomo, Musani, Solomon K, Franceschini, Nora, Rauramaa, Rainer, Alver, Maris, Zee, Phyllis C, Harris, Sarah E, van der Most, Peter J, Nolte, Ilja M, Munroe, Patricia B, Palmer, Nicholette D, Kühnel, Brigitte, Weiss, Stefan, Wen, Wanqing, Hall, Kelly A, Lyytikäinen, Leo-Pekka, O'Connell, Jeff, Eiriksdottir, Gudny, Launer, Lenore J, de Vries, Paul S, Arking, Dan E, Chen, Han, Boerwinkle, Eric, Krieger, Jose E, Schreiner, Pamela J, Sidney, Stephen, Shikany, James M, Rice, Kenneth, Chen, Yii-Der Ida, Gharib, Sina A, Bis, Joshua C, Luik, Annemarie I, Ikram, M Arfan, Uitterlinden, André G, Amin, Najaf, Xu, Hanfei, Levy, Daniel, He, Jiang, Lohman, Kurt K, Zonderman, Alan B, Rice, Treva K, Sims, Mario, Wilson, Gregory, Sofer, Tamar, Rich, Stephen S, Palmas, Walter, Yao, Jie, Guo, Xiuqing, Rotter, Jerome I, Biermasz, Nienke R, Mook-Kanamori, Dennis O, Martin, Lisa W, Barac, Ana, Wallace, Robert B, Gottlieb, Daniel J, Komulainen, Pirjo, Heikkinen, Sami, Mägi, Reedik, Milani, Lili, Metspalu, Andres, Starr, John M, Milaneschi, Yuri, Waken, R J, Gao, Chuan, Waldenberger, Melanie, Peters, Annette, Strauch, Konstantin, Meitinger, Thomas, Roenneberg, Till, Völker, Uwe, Dörr, Marcus, Shu, Xiao-Ou, Mukherjee, Sutapa, Hillman, David R, Kähönen, Mika, Wagenknecht, Lynne E, Gieger, Christian, Grabe, Hans J, Zheng, Wei, Palmer, Lyle J, Lehtimäki, Terho, Gudnason, Vilmundur, Morrison, Alanna C, Pereira, Alexandre C, Fornage, Myriam, Psaty, Bruce M, van Duijn, Cornelia M, Liu, Ching-Ti, Kelly, Tanika N, Evans, Michele K, Bouchard, Claude, Fox, Ervin R, Kooperberg, Charles, Zhu, Xiaofeng, Lakka, Timo A, Esko, Tõnu, North, Kari E, Deary, Ian J, Snieder, Harold, Penninx, Brenda W J H, Gauderman, W James, Rao, Dabeeru C, Redline, Susan, van Heemst, Diana, Wang, Heming, Noordam, Raymond, Cade, Brian E, Schwander, Karen, Winkler, Thomas W, Lee, Jiwon, Sung, Yun Ju, Bentley, Amy R, Manning, Alisa K, Aschard, Hugues, Kilpeläinen, Tuomas O, Ilkov, Marjan, Brown, Michael R, Horimoto, Andrea R, Richard, Melissa, Bartz, Traci M, Vojinovic, Dina, Lim, Elise, Nierenberg, Jovia L, Liu, Yongmei, Chitrala, Kumaraswamynaidu, Rankinen, Tuomo, Musani, Solomon K, Franceschini, Nora, Rauramaa, Rainer, Alver, Maris, Zee, Phyllis C, Harris, Sarah E, van der Most, Peter J, Nolte, Ilja M, Munroe, Patricia B, Palmer, Nicholette D, Kühnel, Brigitte, Weiss, Stefan, Wen, Wanqing, Hall, Kelly A, Lyytikäinen, Leo-Pekka, O'Connell, Jeff, Eiriksdottir, Gudny, Launer, Lenore J, de Vries, Paul S, Arking, Dan E, Chen, Han, Boerwinkle, Eric, Krieger, Jose E, Schreiner, Pamela J, Sidney, Stephen, Shikany, James M, Rice, Kenneth, Chen, Yii-Der Ida, Gharib, Sina A, Bis, Joshua C, Luik, Annemarie I, Ikram, M Arfan, Uitterlinden, André G, Amin, Najaf, Xu, Hanfei, Levy, Daniel, He, Jiang, Lohman, Kurt K, Zonderman, Alan B, Rice, Treva K, Sims, Mario, Wilson, Gregory, Sofer, Tamar, Rich, Stephen S, Palmas, Walter, Yao, Jie, Guo, Xiuqing, Rotter, Jerome I, Biermasz, Nienke R, Mook-Kanamori, Dennis O, Martin, Lisa W, Barac, Ana, Wallace, Robert B, Gottlieb, Daniel J, Komulainen, Pirjo, Heikkinen, Sami, Mägi, Reedik, Milani, Lili, Metspalu, Andres, Starr, John M, Milaneschi, Yuri, Waken, R J, Gao, Chuan, Waldenberger, Melanie, Peters, Annette, Strauch, Konstantin, Meitinger, Thomas, Roenneberg, Till, Völker, Uwe, Dörr, Marcus, Shu, Xiao-Ou, Mukherjee, Sutapa, Hillman, David R, Kähönen, Mika, Wagenknecht, Lynne E, Gieger, Christian, Grabe, Hans J, Zheng, Wei, Palmer, Lyle J, Lehtimäki, Terho, Gudnason, Vilmundur, Morrison, Alanna C, Pereira, Alexandre C, Fornage, Myriam, Psaty, Bruce M, van Duijn, Cornelia M, Liu, Ching-Ti, Kelly, Tanika N, Evans, Michele K, Bouchard, Claude, Fox, Ervin R, Kooperberg, Charles, Zhu, Xiaofeng, Lakka, Timo A, Esko, Tõnu, North, Kari E, Deary, Ian J, Snieder, Harold, Penninx, Brenda W J H, Gauderman, W James, Rao, Dabeeru C, Redline, Susan, and van Heemst, Diana
Abstract: Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
Published: 2021

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