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1. Which older adults are at highest risk of prescribing cascades? A national study of the gabapentinoid–loop diuretic cascade

Author: Growdon, Matthew E, Growdon, Matthew E, Jing, Bocheng, Morris, Earl J, Deardorff, W James, Boscardin, W John, Byers, Amy L, Boockvar, Kenneth S, Steinman, Michael A, Growdon, Matthew E, Growdon, Matthew E, Jing, Bocheng, Morris, Earl J, Deardorff, W James, Boscardin, W John, Byers, Amy L, Boockvar, Kenneth S, and Steinman, Michael A
Abstract: BackgroundPrescribing cascades are important contributors to polypharmacy. Little is known about which older adults are at highest risk of experiencing prescribing cascades. We explored which older veterans are at highest risk of the gabapentinoid (including gabapentin and pregabalin)-loop diuretic (LD) cascade, given the dramatic increase in gabapentinoid prescribing in recent years.MethodsUsing Veterans Affairs and Medicare claims data (2010-2019), we performed a prescription sequence symmetry analysis (PSSA) to assess loop diuretic initiation before and after gabapentinoid initiation among older veterans (≥66 years). To identify the cascade, we calculated the adjusted sequence ratio (aSR), which assesses the temporality of LD relative to gabapentinoid initiation. To explore high-risk groups, we used multivariable logistic regression with prescribing order modeled as a binary dependent variable. We calculated adjusted odds ratios (aORs), measuring the extent to which factors are associated with one prescribing order versus another.ResultsOf 151,442 veterans who initiated a gabapentinoid, there were 1,981 patients who initiated a LD within 6 months after initiating a gabapentinoid compared to 1,599 patients who initiated a LD within 6 months before initiating a gabapentinoid. In the gabapentinoid-LD group, the mean age was 73 years, 98% were male, 13% were Black, 5% were Hispanic, and 80% were White. Patients in each group were similar across patient and health utilization factors (standardized mean difference <0.10 for all comparisons). The aSR was 1.23 (95% CI: 1.13, 1.34), strongly suggesting the cascade's presence. People age ≥85 years were less likely to have the cascade (compared to 66-74 years; aOR 0.74, 95% CI: 0.56-0.96), and people taking ≥10 medications were more likely to have the cascade (compared to 0-4 drugs; aOR 1.39, 95% CI: 1.07-1.82).ConclusionsAmong older adults, those who are younger and taking many medications may be at higher risk of the g
Published: 2024

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
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3. 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

4. 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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5. 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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6. 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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7. 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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8. 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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9. 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

10. Quantifying edge sharpness on stone flakes: comparing mechanical and micro-geometric definitions across multiple raw materials from Olduvai Gorge (Tanzania)

Author: Royal Society (UK), Ministry of Science and Higher Education (Poland), European Commission, Torre Sainz, Ignacio de la [0000-0002-1805-634X], Key, Alastair, Bartkowiak, Tomasz, Macdonald, Danielle A., Mietlinski, Patryk, Gapinski, Bartosz, Torre Sainz, Ignacio de la, Stemp, W. James, Royal Society (UK), Ministry of Science and Higher Education (Poland), European Commission, Torre Sainz, Ignacio de la [0000-0002-1805-634X], Key, Alastair, Bartkowiak, Tomasz, Macdonald, Danielle A., Mietlinski, Patryk, Gapinski, Bartosz, Torre Sainz, Ignacio de la, and Stemp, W. James
Abstract: In line with engineering research focusing on metal tools, techniques to record the attribute of ‘edge sharpness’ on stone tools can include both mechanical and micro-geometric approaches. Mechanically-defined sharpness techniques used in lithic studies are now well established and align with engineering research. The single micro-geometrically-defined technique—tip curvature—is novel relative to approaches used elsewhere, and has not explicitly been tested for its ability to describe the attribute of sharpness. Here, using experimental flakes produced on basalt, chert, and quartzite sourced at Olduvai Gorge (Tanzania), we investigate the relationship between tip curvature and the force and work required to initiate a cut. We do this using controlled cutting tests and analysis of high-resolution microCT scans. Results indicate cutting force and work to display significant dependent relationships with tip curvature, suggesting the latter to be an appropriate metric to record the sharpness of lithic tools. Differences in relationship strength were observed dependent on the measurement scales and edge distances used. Tip curvature is also demonstrated to distinguish between the sharpness of different raw materials. Our data also indicate the predictive relationship between tip curvature and cutting force/work to be one of the strongest yet identified between a stone tool morphological attribute and its cutting performance. Together, this study demonstrates tip curvature to be an appropriate attribute for describing the sharpness of a stone tool’s working edge in diverse raw material scenarios, and that it can be highly predictive of a stone tool’s functional performance.
Published: 2024

11. 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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12. 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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13. 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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14. The Implements of the Blade House:The Function and Symbolic Significance of Laurel-leaf Bifaces from Caves in Central Belize

Author: Stemp, W. James, Awe, Jaime J., Helmke, Christophe, Stemp, W. James, Awe, Jaime J., and Helmke, Christophe
Published: 2024

15. 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

16. 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

17. 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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18. 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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19. 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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20. 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

21. 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

22. 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

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. Global assessment of marine plastic exposure risk for oceanic birds

Author: Clark, Bethany L., Carneiro, Ana P. B., Pearmain, Elizabeth J., Rouyer, Marie-morgane, Clay, Thomas A., Cowger, Win, Phillips, Richard A., Manica, Andrea, Hazin, Carolina, Eriksen, Marcus, González-solís, Jacob, Adams, Josh, Albores-barajas, Yuri V., Alfaro-shigueto, Joanna, Alho, Maria Saldanha, Araujo, Deusa Teixeira, Arcos, José Manuel, Arnould, John P. Y., Barbosa, Nadito J. P., Barbraud, Christophe, Beard, Annalea M., Beck, Jessie, Bell, Elizabeth A., Bennet, Della G., Berlincourt, Maud, Biscoito, Manuel, Bjørnstad, Oskar K., Bolton, Mark, Booth Jones, Katherine A., Borg, John J., Bourgeois, Karen, Bretagnolle, Vincent, Bried, Joël, Briskie, James V., Brooke, M. De L., Brownlie, Katherine C., Bugoni, Leandro, Calabrese, Licia, Campioni, Letizia, Carey, Mark J., Carle, Ryan D., Carlile, Nicholas, Carreiro, Ana R., Catry, Paulo, Catry, Teresa, Cecere, Jacopo G., Ceia, Filipe R., Cherel, Yves, Choi, Chang-yong, Cianchetti-benedetti, Marco, Clarke, Rohan H., Cleeland, Jaimie B., Colodro, Valentina, Congdon, Bradley C., Danielsen, Jóhannis, De Pascalis, Federico, Deakin, Zoe, Dehnhard, Nina, Dell’omo, Giacomo, Delord, Karine, Descamps, Sébastien, Dilley, Ben J., Dinis, Herculano A., Dubos, Jerome, Dunphy, Brendon J., Emmerson, Louise M., Fagundes, Ana Isabel, Fayet, Annette L., Felis, Jonathan J., Fischer, Johannes H., Freeman, Amanda N. D., Fromant, Aymeric, Gaibani, Giorgia, García, David, Gjerdrum, Carina, Gomes, Ivandra Soeli Gonçalves Correia, Forero, Manuela G., Granadeiro, José P., Grecian, W. James, Grémillet, David, Guilford, Tim, Hallgrimsson, Gunnar Thor, Halpin, Luke R., Hansen, Erpur Snær, Hedd, April, Helberg, Morten, Helgason, Halfdan H., Henry, Leeann M., Hereward, Hannah F. R., Hernandez-montero, Marcos, Hindell, Mark A., Hodum, Peter J., Imperio, Simona, Jaeger, Audrey, Jessopp, Mark, Jodice, Patrick G. R., Jones, Carl G., Jones, Christopher W., Jónsson, Jón Einar, Kane, Adam, Kapelj, Sven, Kim, Yuna, Kirk, Holly, Kolbeinsson, Yann, Kraemer, Philipp L., Krüger, Lucas, Lago, Paulo, Landers, Todd J., Lavers, Jennifer L., Le Corre, Matthieu, Leal, Andreia, Louzao, Maite, Madeiros, Jeremy, Magalhães, Maria, Mallory, Mark L., Masello, Juan F., Massa, Bruno, Matsumoto, Sakiko, Mcduie, Fiona, Mcfarlane Tranquilla, Laura, Medrano, Fernando, Metzger, Benjamin J., Militão, Teresa, Montevecchi, William A., Montone, Rosalinda C., Navarro-herrero, Leia, Neves, Verónica C., Nicholls, David G., Nicoll, Malcolm A. C., Norris, Ken, Oppel, Steffen, Oro, Daniel, Owen, Ellie, Padget, Oliver, Paiva, Vítor H., Pala, David, Pereira, Jorge M., Péron, Clara, Petry, Maria V., De Pina, Admilton, Pina, Ariete T. Moreira, Pinet, Patrick, Pistorius, Pierre A., Pollet, Ingrid L., Porter, Benjamin J., Poupart, Timothée A., Powell, Christopher D. L., Proaño, Carolina B., Pujol-casado, Júlia, Quillfeldt, Petra, Quinn, John L., Raine, Andre F., Raine, Helen, Ramírez, Iván, Ramos, Jaime A., Ramos, Raül, Ravache, Andreas, Rayner, Matt J., Reid, Timothy A., Robertson, Gregory J., Rocamora, Gerard J., Rollinson, Dominic P., Ronconi, Robert A., Rotger, Andreu, Rubolini, Diego, Ruhomaun, Kevin, Ruiz, Asunción, Russell, James C., Ryan, Peter G., Saldanha, Sarah, Sanz-aguilar, Ana, Sardà-serra, Mariona, Satgé, Yvan G., Sato, Katsufumi, Schäfer, Wiebke C., Schoombie, Stefan, Shaffer, Scott A., Shah, Nirmal, Shoji, Akiko, Shutler, Dave, Sigurðsson, Ingvar A., Silva, Mónica C., Small, Alison E., Soldatini, Cecilia, Strøm, Hallvard, Surman, Christopher A., Takahashi, Akinori, Tatayah, Vikash R. V., Taylor, Graeme A., Thomas, Robert J., Thompson, David R., Thompson, Paul M., Thórarinsson, Thorkell L., Vicente-sastre, Diego, Vidal, Eric, Wakefield, Ewan D., Waugh, Susan M., Weimerskirch, Henri, Wittmer, Heiko U., Yamamoto, Takashi, Yoda, Ken, Zavalaga, Carlos B., Zino, Francis J., Dias, Maria P., Clark, Bethany L., Carneiro, Ana P. B., Pearmain, Elizabeth J., Rouyer, Marie-morgane, Clay, Thomas A., Cowger, Win, Phillips, Richard A., Manica, Andrea, Hazin, Carolina, Eriksen, Marcus, González-solís, Jacob, Adams, Josh, Albores-barajas, Yuri V., Alfaro-shigueto, Joanna, Alho, Maria Saldanha, Araujo, Deusa Teixeira, Arcos, José Manuel, Arnould, John P. Y., Barbosa, Nadito J. P., Barbraud, Christophe, Beard, Annalea M., Beck, Jessie, Bell, Elizabeth A., Bennet, Della G., Berlincourt, Maud, Biscoito, Manuel, Bjørnstad, Oskar K., Bolton, Mark, Booth Jones, Katherine A., Borg, John J., Bourgeois, Karen, Bretagnolle, Vincent, Bried, Joël, Briskie, James V., Brooke, M. De L., Brownlie, Katherine C., Bugoni, Leandro, Calabrese, Licia, Campioni, Letizia, Carey, Mark J., Carle, Ryan D., Carlile, Nicholas, Carreiro, Ana R., Catry, Paulo, Catry, Teresa, Cecere, Jacopo G., Ceia, Filipe R., Cherel, Yves, Choi, Chang-yong, Cianchetti-benedetti, Marco, Clarke, Rohan H., Cleeland, Jaimie B., Colodro, Valentina, Congdon, Bradley C., Danielsen, Jóhannis, De Pascalis, Federico, Deakin, Zoe, Dehnhard, Nina, Dell’omo, Giacomo, Delord, Karine, Descamps, Sébastien, Dilley, Ben J., Dinis, Herculano A., Dubos, Jerome, Dunphy, Brendon J., Emmerson, Louise M., Fagundes, Ana Isabel, Fayet, Annette L., Felis, Jonathan J., Fischer, Johannes H., Freeman, Amanda N. D., Fromant, Aymeric, Gaibani, Giorgia, García, David, Gjerdrum, Carina, Gomes, Ivandra Soeli Gonçalves Correia, Forero, Manuela G., Granadeiro, José P., Grecian, W. James, Grémillet, David, Guilford, Tim, Hallgrimsson, Gunnar Thor, Halpin, Luke R., Hansen, Erpur Snær, Hedd, April, Helberg, Morten, Helgason, Halfdan H., Henry, Leeann M., Hereward, Hannah F. R., Hernandez-montero, Marcos, Hindell, Mark A., Hodum, Peter J., Imperio, Simona, Jaeger, Audrey, Jessopp, Mark, Jodice, Patrick G. R., Jones, Carl G., Jones, Christopher W., Jónsson, Jón Einar, Kane, Adam, Kapelj, Sven, Kim, Yuna, Kirk, Holly, Kolbeinsson, Yann, Kraemer, Philipp L., Krüger, Lucas, Lago, Paulo, Landers, Todd J., Lavers, Jennifer L., Le Corre, Matthieu, Leal, Andreia, Louzao, Maite, Madeiros, Jeremy, Magalhães, Maria, Mallory, Mark L., Masello, Juan F., Massa, Bruno, Matsumoto, Sakiko, Mcduie, Fiona, Mcfarlane Tranquilla, Laura, Medrano, Fernando, Metzger, Benjamin J., Militão, Teresa, Montevecchi, William A., Montone, Rosalinda C., Navarro-herrero, Leia, Neves, Verónica C., Nicholls, David G., Nicoll, Malcolm A. C., Norris, Ken, Oppel, Steffen, Oro, Daniel, Owen, Ellie, Padget, Oliver, Paiva, Vítor H., Pala, David, Pereira, Jorge M., Péron, Clara, Petry, Maria V., De Pina, Admilton, Pina, Ariete T. Moreira, Pinet, Patrick, Pistorius, Pierre A., Pollet, Ingrid L., Porter, Benjamin J., Poupart, Timothée A., Powell, Christopher D. L., Proaño, Carolina B., Pujol-casado, Júlia, Quillfeldt, Petra, Quinn, John L., Raine, Andre F., Raine, Helen, Ramírez, Iván, Ramos, Jaime A., Ramos, Raül, Ravache, Andreas, Rayner, Matt J., Reid, Timothy A., Robertson, Gregory J., Rocamora, Gerard J., Rollinson, Dominic P., Ronconi, Robert A., Rotger, Andreu, Rubolini, Diego, Ruhomaun, Kevin, Ruiz, Asunción, Russell, James C., Ryan, Peter G., Saldanha, Sarah, Sanz-aguilar, Ana, Sardà-serra, Mariona, Satgé, Yvan G., Sato, Katsufumi, Schäfer, Wiebke C., Schoombie, Stefan, Shaffer, Scott A., Shah, Nirmal, Shoji, Akiko, Shutler, Dave, Sigurðsson, Ingvar A., Silva, Mónica C., Small, Alison E., Soldatini, Cecilia, Strøm, Hallvard, Surman, Christopher A., Takahashi, Akinori, Tatayah, Vikash R. V., Taylor, Graeme A., Thomas, Robert J., Thompson, David R., Thompson, Paul M., Thórarinsson, Thorkell L., Vicente-sastre, Diego, Vidal, Eric, Wakefield, Ewan D., Waugh, Susan M., Weimerskirch, Henri, Wittmer, Heiko U., Yamamoto, Takashi, Yoda, Ken, Zavalaga, Carlos B., Zino, Francis J., and Dias, Maria P.
Abstract: Plastic pollution is distributed patchily around the world’s oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.
Published: 2023
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25. The UCSC Genome Browser database: 2023 update.

Author: Nassar, Luis R, Nassar, Luis R, Barber, Galt P, Benet-Pagès, Anna, Casper, Jonathan, Clawson, Hiram, Diekhans, Mark, Fischer, Clay, Gonzalez, Jairo Navarro, Hinrichs, Angie S, Lee, Brian T, Lee, Christopher M, Muthuraman, Pranav, Nguy, Beagan, Pereira, Tiana, Nejad, Parisa, Perez, Gerardo, Raney, Brian J, Schmelter, Daniel, Speir, Matthew L, Wick, Brittney D, Zweig, Ann S, Haussler, David, Kuhn, Robert M, Haeussler, Maximilian, Kent, W James, Nassar, Luis R, Nassar, Luis R, Barber, Galt P, Benet-Pagès, Anna, Casper, Jonathan, Clawson, Hiram, Diekhans, Mark, Fischer, Clay, Gonzalez, Jairo Navarro, Hinrichs, Angie S, Lee, Brian T, Lee, Christopher M, Muthuraman, Pranav, Nguy, Beagan, Pereira, Tiana, Nejad, Parisa, Perez, Gerardo, Raney, Brian J, Schmelter, Daniel, Speir, Matthew L, Wick, Brittney D, Zweig, Ann S, Haussler, David, Kuhn, Robert M, Haeussler, Maximilian, and Kent, W James
Abstract: The UCSC Genome Browser (https://genome.ucsc.edu) is an omics data consolidator, graphical viewer, and general bioinformatics resource that continues to serve the community as it enters its 23rd year. This year has seen an emphasis in clinical data, with new tracks and an expanded Recommended Track Sets feature on hg38 as well as the addition of a single cell track group. SARS-CoV-2 continues to remain a focus, with regular annotation updates to the browser and continued curation of our phylogenetic sequence placing tool, hgPhyloPlace, whose tree has now reached over 12M sequences. Our GenArk resource has also grown, offering over 2500 hubs and a system for users to request any absent assemblies. We have expanded our bigBarChart display type and created new ways to visualize data via bigRmsk and dynseq display. Displaying custom annotations is now easier due to our chromAlias system which eliminates the requirement for renaming sequence names to the UCSC standard. Users involved in data generation may also be interested in our new tools and trackDb settings which facilitate the creation and display of their custom annotations.
Published: 2023

26. 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

27. 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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28. 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

29. 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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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. 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

31. 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

32. Global assessment of marine plastic exposure risk for oceanic birds

Author: Clark, Bethany L., Carneiro, Ana P. B., Pearmain, Elizabeth J., Rouyer, Marie-morgane, Clay, Thomas A., Cowger, Win, Phillips, Richard A., Manica, Andrea, Hazin, Carolina, Eriksen, Marcus, González-solís, Jacob, Adams, Josh, Albores-barajas, Yuri V., Alfaro-shigueto, Joanna, Alho, Maria Saldanha, Araujo, Deusa Teixeira, Arcos, José Manuel, Arnould, John P. Y., Barbosa, Nadito J. P., Barbraud, Christophe, Beard, Annalea M., Beck, Jessie, Bell, Elizabeth A., Bennet, Della G., Berlincourt, Maud, Biscoito, Manuel, Bjørnstad, Oskar K., Bolton, Mark, Booth Jones, Katherine A., Borg, John J., Bourgeois, Karen, Bretagnolle, Vincent, Bried, Joël, Briskie, James V., Brooke, M. De L., Brownlie, Katherine C., Bugoni, Leandro, Calabrese, Licia, Campioni, Letizia, Carey, Mark J., Carle, Ryan D., Carlile, Nicholas, Carreiro, Ana R., Catry, Paulo, Catry, Teresa, Cecere, Jacopo G., Ceia, Filipe R., Cherel, Yves, Choi, Chang-yong, Cianchetti-benedetti, Marco, Clarke, Rohan H., Cleeland, Jaimie B., Colodro, Valentina, Congdon, Bradley C., Danielsen, Jóhannis, De Pascalis, Federico, Deakin, Zoe, Dehnhard, Nina, Dell’omo, Giacomo, Delord, Karine, Descamps, Sébastien, Dilley, Ben J., Dinis, Herculano A., Dubos, Jerome, Dunphy, Brendon J., Emmerson, Louise M., Fagundes, Ana Isabel, Fayet, Annette L., Felis, Jonathan J., Fischer, Johannes H., Freeman, Amanda N. D., Fromant, Aymeric, Gaibani, Giorgia, García, David, Gjerdrum, Carina, Gomes, Ivandra Soeli Gonçalves Correia, Forero, Manuela G., Granadeiro, José P., Grecian, W. James, Grémillet, David, Guilford, Tim, Hallgrimsson, Gunnar Thor, Halpin, Luke R., Hansen, Erpur Snær, Hedd, April, Helberg, Morten, Helgason, Halfdan H., Henry, Leeann M., Hereward, Hannah F. R., Hernandez-montero, Marcos, Hindell, Mark A., Hodum, Peter J., Imperio, Simona, Jaeger, Audrey, Jessopp, Mark, Jodice, Patrick G. R., Jones, Carl G., Jones, Christopher W., Jónsson, Jón Einar, Kane, Adam, Kapelj, Sven, Kim, Yuna, Kirk, Holly, Kolbeinsson, Yann, Kraemer, Philipp L., Krüger, Lucas, Lago, Paulo, Landers, Todd J., Lavers, Jennifer L., Le Corre, Matthieu, Leal, Andreia, Louzao, Maite, Madeiros, Jeremy, Magalhães, Maria, Mallory, Mark L., Masello, Juan F., Massa, Bruno, Matsumoto, Sakiko, Mcduie, Fiona, Mcfarlane Tranquilla, Laura, Medrano, Fernando, Metzger, Benjamin J., Militão, Teresa, Montevecchi, William A., Montone, Rosalinda C., Navarro-herrero, Leia, Neves, Verónica C., Nicholls, David G., Nicoll, Malcolm A. C., Norris, Ken, Oppel, Steffen, Oro, Daniel, Owen, Ellie, Padget, Oliver, Paiva, Vítor H., Pala, David, Pereira, Jorge M., Péron, Clara, Petry, Maria V., De Pina, Admilton, Pina, Ariete T. Moreira, Pinet, Patrick, Pistorius, Pierre A., Pollet, Ingrid L., Porter, Benjamin J., Poupart, Timothée A., Powell, Christopher D. L., Proaño, Carolina B., Pujol-casado, Júlia, Quillfeldt, Petra, Quinn, John L., Raine, Andre F., Raine, Helen, Ramírez, Iván, Ramos, Jaime A., Ramos, Raül, Ravache, Andreas, Rayner, Matt J., Reid, Timothy A., Robertson, Gregory J., Rocamora, Gerard J., Rollinson, Dominic P., Ronconi, Robert A., Rotger, Andreu, Rubolini, Diego, Ruhomaun, Kevin, Ruiz, Asunción, Russell, James C., Ryan, Peter G., Saldanha, Sarah, Sanz-aguilar, Ana, Sardà-serra, Mariona, Satgé, Yvan G., Sato, Katsufumi, Schäfer, Wiebke C., Schoombie, Stefan, Shaffer, Scott A., Shah, Nirmal, Shoji, Akiko, Shutler, Dave, Sigurðsson, Ingvar A., Silva, Mónica C., Small, Alison E., Soldatini, Cecilia, Strøm, Hallvard, Surman, Christopher A., Takahashi, Akinori, Tatayah, Vikash R. V., Taylor, Graeme A., Thomas, Robert J., Thompson, David R., Thompson, Paul M., Thórarinsson, Thorkell L., Vicente-sastre, Diego, Vidal, Eric, Wakefield, Ewan D., Waugh, Susan M., Weimerskirch, Henri, Wittmer, Heiko U., Yamamoto, Takashi, Yoda, Ken, Zavalaga, Carlos B., Zino, Francis J., Dias, Maria P., Clark, Bethany L., Carneiro, Ana P. B., Pearmain, Elizabeth J., Rouyer, Marie-morgane, Clay, Thomas A., Cowger, Win, Phillips, Richard A., Manica, Andrea, Hazin, Carolina, Eriksen, Marcus, González-solís, Jacob, Adams, Josh, Albores-barajas, Yuri V., Alfaro-shigueto, Joanna, Alho, Maria Saldanha, Araujo, Deusa Teixeira, Arcos, José Manuel, Arnould, John P. Y., Barbosa, Nadito J. P., Barbraud, Christophe, Beard, Annalea M., Beck, Jessie, Bell, Elizabeth A., Bennet, Della G., Berlincourt, Maud, Biscoito, Manuel, Bjørnstad, Oskar K., Bolton, Mark, Booth Jones, Katherine A., Borg, John J., Bourgeois, Karen, Bretagnolle, Vincent, Bried, Joël, Briskie, James V., Brooke, M. De L., Brownlie, Katherine C., Bugoni, Leandro, Calabrese, Licia, Campioni, Letizia, Carey, Mark J., Carle, Ryan D., Carlile, Nicholas, Carreiro, Ana R., Catry, Paulo, Catry, Teresa, Cecere, Jacopo G., Ceia, Filipe R., Cherel, Yves, Choi, Chang-yong, Cianchetti-benedetti, Marco, Clarke, Rohan H., Cleeland, Jaimie B., Colodro, Valentina, Congdon, Bradley C., Danielsen, Jóhannis, De Pascalis, Federico, Deakin, Zoe, Dehnhard, Nina, Dell’omo, Giacomo, Delord, Karine, Descamps, Sébastien, Dilley, Ben J., Dinis, Herculano A., Dubos, Jerome, Dunphy, Brendon J., Emmerson, Louise M., Fagundes, Ana Isabel, Fayet, Annette L., Felis, Jonathan J., Fischer, Johannes H., Freeman, Amanda N. D., Fromant, Aymeric, Gaibani, Giorgia, García, David, Gjerdrum, Carina, Gomes, Ivandra Soeli Gonçalves Correia, Forero, Manuela G., Granadeiro, José P., Grecian, W. James, Grémillet, David, Guilford, Tim, Hallgrimsson, Gunnar Thor, Halpin, Luke R., Hansen, Erpur Snær, Hedd, April, Helberg, Morten, Helgason, Halfdan H., Henry, Leeann M., Hereward, Hannah F. R., Hernandez-montero, Marcos, Hindell, Mark A., Hodum, Peter J., Imperio, Simona, Jaeger, Audrey, Jessopp, Mark, Jodice, Patrick G. R., Jones, Carl G., Jones, Christopher W., Jónsson, Jón Einar, Kane, Adam, Kapelj, Sven, Kim, Yuna, Kirk, Holly, Kolbeinsson, Yann, Kraemer, Philipp L., Krüger, Lucas, Lago, Paulo, Landers, Todd J., Lavers, Jennifer L., Le Corre, Matthieu, Leal, Andreia, Louzao, Maite, Madeiros, Jeremy, Magalhães, Maria, Mallory, Mark L., Masello, Juan F., Massa, Bruno, Matsumoto, Sakiko, Mcduie, Fiona, Mcfarlane Tranquilla, Laura, Medrano, Fernando, Metzger, Benjamin J., Militão, Teresa, Montevecchi, William A., Montone, Rosalinda C., Navarro-herrero, Leia, Neves, Verónica C., Nicholls, David G., Nicoll, Malcolm A. C., Norris, Ken, Oppel, Steffen, Oro, Daniel, Owen, Ellie, Padget, Oliver, Paiva, Vítor H., Pala, David, Pereira, Jorge M., Péron, Clara, Petry, Maria V., De Pina, Admilton, Pina, Ariete T. Moreira, Pinet, Patrick, Pistorius, Pierre A., Pollet, Ingrid L., Porter, Benjamin J., Poupart, Timothée A., Powell, Christopher D. L., Proaño, Carolina B., Pujol-casado, Júlia, Quillfeldt, Petra, Quinn, John L., Raine, Andre F., Raine, Helen, Ramírez, Iván, Ramos, Jaime A., Ramos, Raül, Ravache, Andreas, Rayner, Matt J., Reid, Timothy A., Robertson, Gregory J., Rocamora, Gerard J., Rollinson, Dominic P., Ronconi, Robert A., Rotger, Andreu, Rubolini, Diego, Ruhomaun, Kevin, Ruiz, Asunción, Russell, James C., Ryan, Peter G., Saldanha, Sarah, Sanz-aguilar, Ana, Sardà-serra, Mariona, Satgé, Yvan G., Sato, Katsufumi, Schäfer, Wiebke C., Schoombie, Stefan, Shaffer, Scott A., Shah, Nirmal, Shoji, Akiko, Shutler, Dave, Sigurðsson, Ingvar A., Silva, Mónica C., Small, Alison E., Soldatini, Cecilia, Strøm, Hallvard, Surman, Christopher A., Takahashi, Akinori, Tatayah, Vikash R. V., Taylor, Graeme A., Thomas, Robert J., Thompson, David R., Thompson, Paul M., Thórarinsson, Thorkell L., Vicente-sastre, Diego, Vidal, Eric, Wakefield, Ewan D., Waugh, Susan M., Weimerskirch, Henri, Wittmer, Heiko U., Yamamoto, Takashi, Yoda, Ken, Zavalaga, Carlos B., Zino, Francis J., and Dias, Maria P.
Abstract: Plastic pollution is distributed patchily around the world’s oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.
Published: 2023
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33. 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

34. 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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35. 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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36. 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

37. 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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38. 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

39. 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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40. Mitigation of SARS-CoV-2 by Using Transition Metal Nanozeolites and Quaternary Ammonium Compounds as Antiviral Agents in Suspensions and Soft Fabric Materials

Author: Guerrero-Arguero,Israel, Khan,Siddiqur Rahman, Henry,Brandon M, Garcia-Vilanova,Andreu, Chiem,Kevin, Ye,Chengjin, Shrestha,Sweta, Knight,Deborah, Cristner,Mark, Hill,Shauna, Waldman,W James, Dutta,Prabir K, Torrelles,Jordi B, Martinez-Sobrido,Luis, Nagy,Amber M, Guerrero-Arguero,Israel, Khan,Siddiqur Rahman, Henry,Brandon M, Garcia-Vilanova,Andreu, Chiem,Kevin, Ye,Chengjin, Shrestha,Sweta, Knight,Deborah, Cristner,Mark, Hill,Shauna, Waldman,W James, Dutta,Prabir K, Torrelles,Jordi B, Martinez-Sobrido,Luis, and Nagy,Amber M
Abstract: Israel Guerrero-Arguero,1 Siddiqur Rahman Khan,1 Brandon M Henry,1 Andreu Garcia-Vilanova,1 Kevin Chiem,1 Chengjin Ye,1 Sweta Shrestha,2 Deborah Knight,3 Mark Cristner,4 Shauna Hill,4 W James Waldman,3 Prabir K Dutta,2,5 Jordi B Torrelles,1 Luis Martinez-Sobrido,1 Amber M Nagy1,4 1Disease Intervention & Prevention and Population Health Programs, Texas Biomedical Research Institute, San Antonio, TX, USA; 2ZeoVation Inc., Columbus, OH, USA; 3Department of Pathology, The Ohio State University, Columbus, OH, USA; 4Chief Scientistâs Office of Science and Technology, 59th Medical Wing, Joint Base San Antonio-Lackland, San Antonio, TX, USA; 5Department of Chemistry, The Ohio State University, Columbus, OH, USACorrespondence: Prabir K Dutta; Amber M Nagy, Email dutta.1@osu.edu; AMallory@txbiomed.orgIntroduction: The coronavirus disease 2019 (COVID-19) pandemic has demonstrated the need for novel, affordable, and efficient reagents to help reduce viral transmission, especially in high-risk environments including medical treatment facilities, close quarters, and austere settings. We examined transition-metal nanozeolite suspensions and quaternary ammonium compounds as an antiviral surface coating for various textile materials.Methods: Zeolites are crystalline porous aluminosilicate materials, with the ability of ion-exchanging different cations. Nanozeolites (30 nm) were synthesized and then ion-exchanged with silver, zinc and copper ions. Benzalkonium nitrate (BZN) was examined as the quaternary ammonium ion (quat). Suspensions of these materials were tested for antiviral activity towards SARS-CoV-2 using plaque assay and immunostaining. Suspensions of the nanozeolite and quat were deposited on polyester and cotton fabrics and the ability of these textiles towards neutralizing SARS-CoV-2 was examined.Results: We hypothesized that transition metal ion containing zeolites, particularly silver and zinc (AM30) and silver and copper (AV30), would be effective in reducing th
Published: 2023

41. Global assessment of marine plastic exposure risk for oceanic birds

Author: Cambridge Conservation Initiative, Fondation Prince Albert II de Monaco, Natural Environment Research Council (UK), Clark, Bethany L., Carneiro, Ana P. B., Pearmain, Elizabeth J., Rouyer, Marie-Morgane, Clay, Thomas A., Cowger, Win, Phillips, Richard A., Manica, Andrea, Hazin, Carolina, Eriksen, Marcus, González-Solís, Jacob, Adams, Josh, Albores-Barajas, Yuri V., Alfaro-Shigueto, Joanna, Alho, Maria Saldanha, Araujo, Deusa Teixeira, Arcos, José Manuel, Arnould, John P. Y., Barbosa, Nadito J. P., Barbraud, Christophe, Beard, Annalea M., Beck, Jessie, Bell, Elizabeth A., Bennet, Della G., Berlincourt, Maud, Biscoito, Manuel, Bjørnstad, Oskar K., Bolton, Mark, Booth Jones, Katherine A., Borg, John J., Bourgeois, Karen, Bretagnolle, Vincent, Bried, Joël, Briskie, James V., Brooke, M de L., Brownlie, Katherine C., Bugoni, Leandro, Calabrese, Licia, Campioni, Letizia, Carey, Mark J., Carle, Ryan D., Carlile, Nicholas, Carreiro, Ana R., Catry, Paulo, Catry, Teresa, Cecere, Jacopo G., Ceia, Filipe R., Cherel, Yves, Choi, Chang-Yong, Cianchetti-Benedetti, Marco, Clarke, Rohan H., Cleeland, Jaimie B., Colodro, Valentina, Congdon, Bradley C., Danielsen, Jóhannis, De Pascalis, Federico, Deakin, Zoe, Dehnhard, Nina, Dell'Omo, Giacomo, Delord, Karine, Descamps, Sébastien, Dilley, Ben J., Dinis, Herculano A., Dubos, Jerome, Dunphy, Brendon J., Emmerson, Louise M., Fagundes, Ana Isabel, Fayet, Annette L., Felis, Jonathan J., Fischer, Johannes H., Freeman, Amanda N. D., Fromant, Aymeric, Gaibani, Giorgia, García, David, Gjerdrum, Carina, Gomes, Ivandra Soeli Gonçalves Correia, Forero, Manuela G., Granadeiro, José P., Grecian, W James, Grémillet, David, Guilford, Tim, Hallgrimsson, Gunnar Thor, Halpin, Luke R., Hansen, Erpur Snær, Hedd, April, Helberg, Morten, Helgason, Halfdan H., Henry, Leeann M., Hereward, Hannah F. R., Hernandez-Montero, Marcos, Hindell, Mark A., Hodum, Peter J., Imperio, Simona, Jaeger, Audrey, Jessopp, Mark, Jodice, Patrick G. R., Jones, Carl G, Jones, Christopher W., Jónsson, Jón Einar, Kane, Adam, Kapelj, Sven, Kim, Yuna, Kirk, Holly, Kolbeinsson, Yann, Kraemer, Philipp L., Krüger, Lucas, Lago, Paulo, Landers, Todd J., Lavers, Jennifer L., Le Corre, Matthieu, Leal, Andreia, Louzao, Maite, Madeiros, Jeremy, Magalhães, Maria, Mallory, Mark L., Masello, Juan F., Massa, Bruno, Matsumoto, Sakiko, McDuie, Fiona, McFarlane Tranquilla, Laura, Medrano, Fernando, Metzger, Benjamin J., Militão, Teresa, Montevecchi, William A., Montone, Rosalinda C., Navarro-Herrero, Leia, Neves, Verónica C., Nicholls, David G., Nicoll, Malcolm A .C., Norris, Ken, Oppel, Steffen, Oro, Daniel, Owen, Ellie, Padget, Oliver, Paiva, Vítor H., Pala, David, Pereira, Jorge M., Péron, Clara, Petry, Maria V., de Pina, Admilton, Pina, Ariete T Moreira, Pinet, Patrick, Pistorius, Pierre A., Pollet, Ingrid L., Porter, Benjamin J., Poupart, Timothée A., Powell, Christopher D. L., Proaño, Carolina B., Pujol-Casado, Júlia, Quillfeldt, Petra, Quinn, John L., Raine, Andre F., Raine, Helen, Ramírez, Iván, Ramos, Jaime A., Ramos, Raül, Ravache, Andreas, Rayner, Matt J., Reid, Timothy A., Robertson, Gregory J., Rocamora, Gerard J., Rollinson, Dominic P., Ronconi, Robert A., Rotger, Andreu, Rubolini, Diego, Ruhomaun, Kevin, Ruiz, Asunción, Russell, James C., Ryan, Peter G., Saldanha, Sarah, Sanz-Aguilar, Ana, Sardà-Serra, Mariona, Satgé, Yvan G., Sato, Katsufumi, Schäfer, Wiebke C., Schoombie, Stefan, Shaffer, Scott A., Shah, Nirmal, Shoji, Akiko, Shutler, Dave, Sigurðsson, Ingvar A., Silva, Mónica C., Small, Alison E., Soldatini, Cecilia, Strøm, Hallvard, Surman, Christopher A., Takahashi, Akinori, Tatayah, Vikash R. V., Taylor, Graeme A., Thomas, Robert J., Thompson, David R., Thompson, Paul M., Thórarinsson, Thorkell L., Vicente-Sastre, Diego, Vidal, Eric, Wakefield, Ewan D., Waugh, Susan M., Weimerskirch, Henri, Wittmer, Heiko U., Yamamoto, Takashi, Yoda, Ken, Zavalaga, Carlos B., Zino, Francis J., Dias, Maria P., Cambridge Conservation Initiative, Fondation Prince Albert II de Monaco, Natural Environment Research Council (UK), Clark, Bethany L., Carneiro, Ana P. B., Pearmain, Elizabeth J., Rouyer, Marie-Morgane, Clay, Thomas A., Cowger, Win, Phillips, Richard A., Manica, Andrea, Hazin, Carolina, Eriksen, Marcus, González-Solís, Jacob, Adams, Josh, Albores-Barajas, Yuri V., Alfaro-Shigueto, Joanna, Alho, Maria Saldanha, Araujo, Deusa Teixeira, Arcos, José Manuel, Arnould, John P. Y., Barbosa, Nadito J. P., Barbraud, Christophe, Beard, Annalea M., Beck, Jessie, Bell, Elizabeth A., Bennet, Della G., Berlincourt, Maud, Biscoito, Manuel, Bjørnstad, Oskar K., Bolton, Mark, Booth Jones, Katherine A., Borg, John J., Bourgeois, Karen, Bretagnolle, Vincent, Bried, Joël, Briskie, James V., Brooke, M de L., Brownlie, Katherine C., Bugoni, Leandro, Calabrese, Licia, Campioni, Letizia, Carey, Mark J., Carle, Ryan D., Carlile, Nicholas, Carreiro, Ana R., Catry, Paulo, Catry, Teresa, Cecere, Jacopo G., Ceia, Filipe R., Cherel, Yves, Choi, Chang-Yong, Cianchetti-Benedetti, Marco, Clarke, Rohan H., Cleeland, Jaimie B., Colodro, Valentina, Congdon, Bradley C., Danielsen, Jóhannis, De Pascalis, Federico, Deakin, Zoe, Dehnhard, Nina, Dell'Omo, Giacomo, Delord, Karine, Descamps, Sébastien, Dilley, Ben J., Dinis, Herculano A., Dubos, Jerome, Dunphy, Brendon J., Emmerson, Louise M., Fagundes, Ana Isabel, Fayet, Annette L., Felis, Jonathan J., Fischer, Johannes H., Freeman, Amanda N. D., Fromant, Aymeric, Gaibani, Giorgia, García, David, Gjerdrum, Carina, Gomes, Ivandra Soeli Gonçalves Correia, Forero, Manuela G., Granadeiro, José P., Grecian, W James, Grémillet, David, Guilford, Tim, Hallgrimsson, Gunnar Thor, Halpin, Luke R., Hansen, Erpur Snær, Hedd, April, Helberg, Morten, Helgason, Halfdan H., Henry, Leeann M., Hereward, Hannah F. R., Hernandez-Montero, Marcos, Hindell, Mark A., Hodum, Peter J., Imperio, Simona, Jaeger, Audrey, Jessopp, Mark, Jodice, Patrick G. R., Jones, Carl G, Jones, Christopher W., Jónsson, Jón Einar, Kane, Adam, Kapelj, Sven, Kim, Yuna, Kirk, Holly, Kolbeinsson, Yann, Kraemer, Philipp L., Krüger, Lucas, Lago, Paulo, Landers, Todd J., Lavers, Jennifer L., Le Corre, Matthieu, Leal, Andreia, Louzao, Maite, Madeiros, Jeremy, Magalhães, Maria, Mallory, Mark L., Masello, Juan F., Massa, Bruno, Matsumoto, Sakiko, McDuie, Fiona, McFarlane Tranquilla, Laura, Medrano, Fernando, Metzger, Benjamin J., Militão, Teresa, Montevecchi, William A., Montone, Rosalinda C., Navarro-Herrero, Leia, Neves, Verónica C., Nicholls, David G., Nicoll, Malcolm A .C., Norris, Ken, Oppel, Steffen, Oro, Daniel, Owen, Ellie, Padget, Oliver, Paiva, Vítor H., Pala, David, Pereira, Jorge M., Péron, Clara, Petry, Maria V., de Pina, Admilton, Pina, Ariete T Moreira, Pinet, Patrick, Pistorius, Pierre A., Pollet, Ingrid L., Porter, Benjamin J., Poupart, Timothée A., Powell, Christopher D. L., Proaño, Carolina B., Pujol-Casado, Júlia, Quillfeldt, Petra, Quinn, John L., Raine, Andre F., Raine, Helen, Ramírez, Iván, Ramos, Jaime A., Ramos, Raül, Ravache, Andreas, Rayner, Matt J., Reid, Timothy A., Robertson, Gregory J., Rocamora, Gerard J., Rollinson, Dominic P., Ronconi, Robert A., Rotger, Andreu, Rubolini, Diego, Ruhomaun, Kevin, Ruiz, Asunción, Russell, James C., Ryan, Peter G., Saldanha, Sarah, Sanz-Aguilar, Ana, Sardà-Serra, Mariona, Satgé, Yvan G., Sato, Katsufumi, Schäfer, Wiebke C., Schoombie, Stefan, Shaffer, Scott A., Shah, Nirmal, Shoji, Akiko, Shutler, Dave, Sigurðsson, Ingvar A., Silva, Mónica C., Small, Alison E., Soldatini, Cecilia, Strøm, Hallvard, Surman, Christopher A., Takahashi, Akinori, Tatayah, Vikash R. V., Taylor, Graeme A., Thomas, Robert J., Thompson, David R., Thompson, Paul M., Thórarinsson, Thorkell L., Vicente-Sastre, Diego, Vidal, Eric, Wakefield, Ewan D., Waugh, Susan M., Weimerskirch, Henri, Wittmer, Heiko U., Yamamoto, Takashi, Yoda, Ken, Zavalaga, Carlos B., Zino, Francis J., and Dias, Maria P.
Abstract: Plastic pollution is distributed patchily around the world's oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.
Published: 2023

42. 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

43. The UCSC Genome Browser database: 2022 update.

Author: Lee, Brian T, Lee, Brian T, Barber, Galt P, Benet-Pagès, Anna, Casper, Jonathan, Clawson, Hiram, Diekhans, Mark, Fischer, Clay, Gonzalez, Jairo Navarro, Hinrichs, Angie S, Lee, Christopher M, Muthuraman, Pranav, Nassar, Luis R, Nguy, Beagan, Pereira, Tiana, Perez, Gerardo, Raney, Brian J, Rosenbloom, Kate R, Schmelter, Daniel, Speir, Matthew L, Wick, Brittney D, Zweig, Ann S, Haussler, David, Kuhn, Robert M, Haeussler, Maximilian, Kent, W James, Lee, Brian T, Lee, Brian T, Barber, Galt P, Benet-Pagès, Anna, Casper, Jonathan, Clawson, Hiram, Diekhans, Mark, Fischer, Clay, Gonzalez, Jairo Navarro, Hinrichs, Angie S, Lee, Christopher M, Muthuraman, Pranav, Nassar, Luis R, Nguy, Beagan, Pereira, Tiana, Perez, Gerardo, Raney, Brian J, Rosenbloom, Kate R, Schmelter, Daniel, Speir, Matthew L, Wick, Brittney D, Zweig, Ann S, Haussler, David, Kuhn, Robert M, Haeussler, Maximilian, and Kent, W James
Abstract: The UCSC Genome Browser, https://genome.ucsc.edu, is a graphical viewer for exploring genome annotations. The website provides integrated tools for visualizing, comparing, analyzing, and sharing both publicly available and user-generated genomic datasets. Data highlights this year include a collection of easily accessible public hub assemblies on new organisms, now featuring BLAT alignment and PCR capabilities, and new and updated clinical tracks (gnomAD, DECIPHER, CADD, REVEL). We introduced a new Track Sets feature and enhanced variant displays to aid in the interpretation of clinical data. We also added a tool to rapidly place new SARS-CoV-2 genomes in a global phylogenetic tree enabling researchers to view the context of emerging mutations in our SARS-CoV-2 Genome Browser. Other new software focuses on usability features, including more informative mouseover displays and new fonts.
Published: 2022

44. The UCSC Genome Browser database: 2022 update.

Author: Lee, Brian T, Lee, Brian T, Barber, Galt P, Benet-Pagès, Anna, Casper, Jonathan, Clawson, Hiram, Diekhans, Mark, Fischer, Clay, Gonzalez, Jairo Navarro, Hinrichs, Angie S, Lee, Christopher M, Muthuraman, Pranav, Nassar, Luis R, Nguy, Beagan, Pereira, Tiana, Perez, Gerardo, Raney, Brian J, Rosenbloom, Kate R, Schmelter, Daniel, Speir, Matthew L, Wick, Brittney D, Zweig, Ann S, Haussler, David, Kuhn, Robert M, Haeussler, Maximilian, Kent, W James, Lee, Brian T, Lee, Brian T, Barber, Galt P, Benet-Pagès, Anna, Casper, Jonathan, Clawson, Hiram, Diekhans, Mark, Fischer, Clay, Gonzalez, Jairo Navarro, Hinrichs, Angie S, Lee, Christopher M, Muthuraman, Pranav, Nassar, Luis R, Nguy, Beagan, Pereira, Tiana, Perez, Gerardo, Raney, Brian J, Rosenbloom, Kate R, Schmelter, Daniel, Speir, Matthew L, Wick, Brittney D, Zweig, Ann S, Haussler, David, Kuhn, Robert M, Haeussler, Maximilian, and Kent, W James
Abstract: The UCSC Genome Browser, https://genome.ucsc.edu, is a graphical viewer for exploring genome annotations. The website provides integrated tools for visualizing, comparing, analyzing, and sharing both publicly available and user-generated genomic datasets. Data highlights this year include a collection of easily accessible public hub assemblies on new organisms, now featuring BLAT alignment and PCR capabilities, and new and updated clinical tracks (gnomAD, DECIPHER, CADD, REVEL). We introduced a new Track Sets feature and enhanced variant displays to aid in the interpretation of clinical data. We also added a tool to rapidly place new SARS-CoV-2 genomes in a global phylogenetic tree enabling researchers to view the context of emerging mutations in our SARS-CoV-2 Genome Browser. Other new software focuses on usability features, including more informative mouseover displays and new fonts.
Published: 2022

45. 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

46. 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

47. 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

48. Revisiting lithic edge characterization with microCT: Multiscale study of edge curvature, re-entrant features, and profile geometry on Olduvai Gorge quartzite flakes

Author: European Research Council, National Science Foundation (US), Ministry of Science and Higher Education (Poland), Torre, Ignacio de la [0000-0002-1805-634X], Macdonald, Danielle A., Bartkowiak, Tomasz, Mendak, Michal, Stemp, W. James, Key, Alastair, Torre Sainz, Ignacio de la, Wieczorowski, Michal, European Research Council, National Science Foundation (US), Ministry of Science and Higher Education (Poland), Torre, Ignacio de la [0000-0002-1805-634X], Macdonald, Danielle A., Bartkowiak, Tomasz, Mendak, Michal, Stemp, W. James, Key, Alastair, Torre Sainz, Ignacio de la, and Wieczorowski, Michal
Abstract: The angle and shape of lithic tool edges have long been used as a method of inferring prehistoric tool function. However, accurately measuring and characterizing edge angles of lithic tools is notoriously difficult. Studies using goniometers, calipers, or morphometrics often rely on two-dimensional representations of edges. Furthermore, there have been limited attempts to quantitatively document stone tool edges based on surface metrology, most notably edge curvature. In this study, we use microCT to capture models of the complex geometry, or ‘freeform’ surfaces, of experimental quartzite flakes from Olduvai Gorge (Tanzania) to document and mathematically calculate edge curvature using multiscalar length-scale analysis. Through this analysis, we also explore the quantification of re-entrant (overhang) features on lithic edge cross-sections. On lithic tools, especially coarse-grained rocks with complex surface topographies, such as quartzite, traditional techniques for edge angle measurement are incapable of capturing re-entrant features on edge profiles. Here we present the first archaeological study that addresses the measurement of these re-entrant features, using novel length-scale and curvature analysis methods of calculating edge angles for complex freeform surfaces. With these new methods for measuring edge angles, we can consider the impact of complex geometry, including re-entrant features, on the function of lithic tools in the past.
Published: 2022

49. Definitions, methods, and applications in interpretable machine learning.

Author: Murdoch, W James, Murdoch, W James, Singh, Chandan, Kumbier, Karl, Abbasi-Asl, Reza, Yu, Bin, Murdoch, W James, Murdoch, W James, Singh, Chandan, Kumbier, Karl, Abbasi-Asl, Reza, and Yu, Bin
Abstract: Machine-learning models have demonstrated great success in learning complex patterns that enable them to make predictions about unobserved data. In addition to using models for prediction, the ability to interpret what a model has learned is receiving an increasing amount of attention. However, this increased focus has led to considerable confusion about the notion of interpretability. In particular, it is unclear how the wide array of proposed interpretation methods are related and what common concepts can be used to evaluate them. We aim to address these concerns by defining interpretability in the context of machine learning and introducing the predictive, descriptive, relevant (PDR) framework for discussing interpretations. The PDR framework provides 3 overarching desiderata for evaluation: predictive accuracy, descriptive accuracy, and relevancy, with relevancy judged relative to a human audience. Moreover, to help manage the deluge of interpretation methods, we introduce a categorization of existing techniques into model-based and post hoc categories, with subgroups including sparsity, modularity, and simulatability. To demonstrate how practitioners can use the PDR framework to evaluate and understand interpretations, we provide numerous real-world examples. These examples highlight the often underappreciated role played by human audiences in discussions of interpretability. Finally, based on our framework, we discuss limitations of existing methods and directions for future work. We hope that this work will provide a common vocabulary that will make it easier for both practitioners and researchers to discuss and choose from the full range of interpretation methods.
Published: 2019

50. Definitions, methods, and applications in interpretable machine learning.

Author: Murdoch, W James, Murdoch, W James, Singh, Chandan, Kumbier, Karl, Abbasi-Asl, Reza, Yu, Bin, Murdoch, W James, Murdoch, W James, Singh, Chandan, Kumbier, Karl, Abbasi-Asl, Reza, and Yu, Bin
Abstract: Machine-learning models have demonstrated great success in learning complex patterns that enable them to make predictions about unobserved data. In addition to using models for prediction, the ability to interpret what a model has learned is receiving an increasing amount of attention. However, this increased focus has led to considerable confusion about the notion of interpretability. In particular, it is unclear how the wide array of proposed interpretation methods are related and what common concepts can be used to evaluate them. We aim to address these concerns by defining interpretability in the context of machine learning and introducing the predictive, descriptive, relevant (PDR) framework for discussing interpretations. The PDR framework provides 3 overarching desiderata for evaluation: predictive accuracy, descriptive accuracy, and relevancy, with relevancy judged relative to a human audience. Moreover, to help manage the deluge of interpretation methods, we introduce a categorization of existing techniques into model-based and post hoc categories, with subgroups including sparsity, modularity, and simulatability. To demonstrate how practitioners can use the PDR framework to evaluate and understand interpretations, we provide numerous real-world examples. These examples highlight the often underappreciated role played by human audiences in discussions of interpretability. Finally, based on our framework, we discuss limitations of existing methods and directions for future work. We hope that this work will provide a common vocabulary that will make it easier for both practitioners and researchers to discuss and choose from the full range of interpretation methods.
Published: 2019

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