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1. 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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2. 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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3. Body size and risk of colorectal cancer molecular defined subtypes and pathways : mendelian randomization analyses

Author: Papadimitriou, Nikos, Qu, Conghui, Harrison, Tabitha A., Bever, Alaina M., Martin, Richard M., Tsilidis, Konstantinos K., Newcomb, Polly A., Thibodeau, Stephen N., Newton, Christina C., Um, Caroline Y., Obón-Santacana, Mireia, Moreno, Victor, Brenner, Hermann, Mandic, Marko, Chang-Claude, Jenny, Hoffmeister, Michael, Pellatt, Andrew J., Schoen, Robert E., Harlid, Sophia, Ogino, Shuji, Ugai, Tomotaka, Buchanan, Daniel D., Lynch, Brigid M., Gruber, Stephen B., Cao, Yin, Hsu, Li, Huyghe, Jeroen R., Lin, Yi, Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Zaidi, Syed H., Toland, Amanda E., Berndt, Sonja I., Huang, Wen-Yi, Aglago, Elom K., Drew, David A., French, Amy J., Georgeson, Peter, Giannakis, Marios, Hullar, Meredith, Nowak, Johnathan A., Thomas, Claire E., Le Marchand, Loic, Cheng, Iona, Gallinger, Steven, Jenkins, Mark A., Gunter, Marc J., Campbell, Peter T., Peters, Ulrike, Song, Mingyang, Phipps, Amanda I., Murphy, Neil, Papadimitriou, Nikos, Qu, Conghui, Harrison, Tabitha A., Bever, Alaina M., Martin, Richard M., Tsilidis, Konstantinos K., Newcomb, Polly A., Thibodeau, Stephen N., Newton, Christina C., Um, Caroline Y., Obón-Santacana, Mireia, Moreno, Victor, Brenner, Hermann, Mandic, Marko, Chang-Claude, Jenny, Hoffmeister, Michael, Pellatt, Andrew J., Schoen, Robert E., Harlid, Sophia, Ogino, Shuji, Ugai, Tomotaka, Buchanan, Daniel D., Lynch, Brigid M., Gruber, Stephen B., Cao, Yin, Hsu, Li, Huyghe, Jeroen R., Lin, Yi, Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Zaidi, Syed H., Toland, Amanda E., Berndt, Sonja I., Huang, Wen-Yi, Aglago, Elom K., Drew, David A., French, Amy J., Georgeson, Peter, Giannakis, Marios, Hullar, Meredith, Nowak, Johnathan A., Thomas, Claire E., Le Marchand, Loic, Cheng, Iona, Gallinger, Steven, Jenkins, Mark A., Gunter, Marc J., Campbell, Peter T., Peters, Ulrike, Song, Mingyang, Phipps, Amanda I., and Murphy, Neil
Abstract: Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, Americ
Published: 2024
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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
Full Text: View/download PDF

5. Body size and risk of colorectal cancer molecular defined subtypes and pathways : mendelian randomization analyses

Author: Papadimitriou, Nikos, Qu, Conghui, Harrison, Tabitha A., Bever, Alaina M., Martin, Richard M., Tsilidis, Konstantinos K., Newcomb, Polly A., Thibodeau, Stephen N., Newton, Christina C., Um, Caroline Y., Obón-Santacana, Mireia, Moreno, Victor, Brenner, Hermann, Mandic, Marko, Chang-Claude, Jenny, Hoffmeister, Michael, Pellatt, Andrew J., Schoen, Robert E., Harlid, Sophia, Ogino, Shuji, Ugai, Tomotaka, Buchanan, Daniel D., Lynch, Brigid M., Gruber, Stephen B., Cao, Yin, Hsu, Li, Huyghe, Jeroen R., Lin, Yi, Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Zaidi, Syed H., Toland, Amanda E., Berndt, Sonja I., Huang, Wen-Yi, Aglago, Elom K., Drew, David A., French, Amy J., Georgeson, Peter, Giannakis, Marios, Hullar, Meredith, Nowak, Johnathan A., Thomas, Claire E., Le Marchand, Loic, Cheng, Iona, Gallinger, Steven, Jenkins, Mark A., Gunter, Marc J., Campbell, Peter T., Peters, Ulrike, Song, Mingyang, Phipps, Amanda I., Murphy, Neil, Papadimitriou, Nikos, Qu, Conghui, Harrison, Tabitha A., Bever, Alaina M., Martin, Richard M., Tsilidis, Konstantinos K., Newcomb, Polly A., Thibodeau, Stephen N., Newton, Christina C., Um, Caroline Y., Obón-Santacana, Mireia, Moreno, Victor, Brenner, Hermann, Mandic, Marko, Chang-Claude, Jenny, Hoffmeister, Michael, Pellatt, Andrew J., Schoen, Robert E., Harlid, Sophia, Ogino, Shuji, Ugai, Tomotaka, Buchanan, Daniel D., Lynch, Brigid M., Gruber, Stephen B., Cao, Yin, Hsu, Li, Huyghe, Jeroen R., Lin, Yi, Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Zaidi, Syed H., Toland, Amanda E., Berndt, Sonja I., Huang, Wen-Yi, Aglago, Elom K., Drew, David A., French, Amy J., Georgeson, Peter, Giannakis, Marios, Hullar, Meredith, Nowak, Johnathan A., Thomas, Claire E., Le Marchand, Loic, Cheng, Iona, Gallinger, Steven, Jenkins, Mark A., Gunter, Marc J., Campbell, Peter T., Peters, Ulrike, Song, Mingyang, Phipps, Amanda I., and Murphy, Neil
Abstract: Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, Americ
Published: 2024
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6. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author: Fernandez-Rozadilla, Ceres, Timofeeva, Maria, Chen, Zhishan, Law, Philip, Thomas, Minta, Schmit, Stephanie, Díez-Obrero, Virginia, Hsu, Li, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah, Svinti, Victoria, Donnelly, Kevin, Farrington, Susan, Blackmur, James, Vaughan-Shaw, Peter, Shu, Xiao-ou, Long, Jirong, Cai, Qiuyin, Guo, Xingyi, Lu, Yingchang, Broderick, Peter, Studd, James, Huyghe, Jeroen, Harrison, Tabitha, Conti, David, Dampier, Christopher, Devall, Mathew, Schumacher, Fredrick, Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Moratalla-Navarro, Ferran, 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, Jenkins, Mark, Win, Aung Ko, Pai, Rish, Figueiredo, Jane, Haile, Robert, Gallinger, Steven, Woods, Michael, Newcomb, Polly, Duggan, David, Cheadle, Jeremy, Kaplan, Richard, Maughan, Timothy, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Lukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri, Rissanen, Harri, Pukkala, Eero, Eriksson, Johan, Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Zanke, Brent, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie, Ruiz-Narvaez, Edward, Palmer, Julie, Buchanan, Daniel, Platz, Elizabeth, Visvanathan, Kala, Ulrich, Cornelia, Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter, Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha, Potter, John, Tsilidis, Konstantinos, Schulze, Matthias, Gunter, Marc, Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Stern, Mariana, Pardamean, Bens, Bishop, Timothy, Giles, Graham, Southey, Melissa, Idos, Gregory, McDonnell, Kevin, Abu-Ful, Zomoroda, Greenson, Joel, Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope, van Guelpen, Bethany, Hudson, Thomas, Hampel, Heather, Pearlman, Rachel, Berndt, Sonja, Hayes, Richard, Martinez, Marie Elena, Thomas, Sushma, Corley, Douglas, Pharoah, Paul, Larsson, Susanna, Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly, Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew, Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David, Joshi, Amit, Schafmayer, Clemens, Scacheri, Peter, Kundaje, Anshul, Nickerson, Deborah, Schoen, Robert, Hampe, Jochen, Stadler, Zsofia, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Papadopoulos, Nickolas, Edlund, Chistopher, Gauderman, William, Thomas, Duncan, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen, van Duijnhoven, Franzel, Feskens, Edith, Sakoda, Lori, Gago-Dominguez, Manuela, Wolk, Alicja, Naccarati, Alessio, Pardini, Barbara, FitzGerald, Liesel, Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie, Kooperberg, Charles, Li, Christopher, Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Tangen, Catherine, Mardis, Elaine, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Haiman, Christopher, Le Marchand, Loic, Wu, Anna, Qu, Chenxu, McNeil, Caroline, Coetzee, Gerhard, Hayward, Caroline, Deary, Ian, Harris, Sarah, Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Moreno, Victor, Casey, Graham, Gruber, Stephen, Tomlinson, Ian, Zheng, Wei, Dunlop, Malcolm, Houlston, Richard, Peters, Ulrike, Fernandez-Rozadilla, Ceres, Timofeeva, Maria, Chen, Zhishan, Law, Philip, Thomas, Minta, Schmit, Stephanie, Díez-Obrero, Virginia, Hsu, Li, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah, Svinti, Victoria, Donnelly, Kevin, Farrington, Susan, Blackmur, James, Vaughan-Shaw, Peter, Shu, Xiao-ou, Long, Jirong, Cai, Qiuyin, Guo, Xingyi, Lu, Yingchang, Broderick, Peter, Studd, James, Huyghe, Jeroen, Harrison, Tabitha, Conti, David, Dampier, Christopher, Devall, Mathew, Schumacher, Fredrick, Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Moratalla-Navarro, Ferran, 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, Jenkins, Mark, Win, Aung Ko, Pai, Rish, Figueiredo, Jane, Haile, Robert, Gallinger, Steven, Woods, Michael, Newcomb, Polly, Duggan, David, Cheadle, Jeremy, Kaplan, Richard, Maughan, Timothy, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Lukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri, Rissanen, Harri, Pukkala, Eero, Eriksson, Johan, Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Zanke, Brent, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie, Ruiz-Narvaez, Edward, Palmer, Julie, Buchanan, Daniel, Platz, Elizabeth, Visvanathan, Kala, Ulrich, Cornelia, Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter, Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha, Potter, John, Tsilidis, Konstantinos, Schulze, Matthias, Gunter, Marc, Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Stern, Mariana, Pardamean, Bens, Bishop, Timothy, Giles, Graham, Southey, Melissa, Idos, Gregory, McDonnell, Kevin, Abu-Ful, Zomoroda, Greenson, Joel, Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope, van Guelpen, Bethany, Hudson, Thomas, Hampel, Heather, Pearlman, Rachel, Berndt, Sonja, Hayes, Richard, Martinez, Marie Elena, Thomas, Sushma, Corley, Douglas, Pharoah, Paul, Larsson, Susanna, Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly, Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew, Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David, Joshi, Amit, Schafmayer, Clemens, Scacheri, Peter, Kundaje, Anshul, Nickerson, Deborah, Schoen, Robert, Hampe, Jochen, Stadler, Zsofia, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Papadopoulos, Nickolas, Edlund, Chistopher, Gauderman, William, Thomas, Duncan, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen, van Duijnhoven, Franzel, Feskens, Edith, Sakoda, Lori, Gago-Dominguez, Manuela, Wolk, Alicja, Naccarati, Alessio, Pardini, Barbara, FitzGerald, Liesel, Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie, Kooperberg, Charles, Li, Christopher, Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Tangen, Catherine, Mardis, Elaine, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Haiman, Christopher, Le Marchand, Loic, Wu, Anna, Qu, Chenxu, McNeil, Caroline, Coetzee, Gerhard, Hayward, Caroline, Deary, Ian, Harris, Sarah, Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Moreno, Victor, Casey, Graham, Gruber, Stephen, Tomlinson, Ian, Zheng, Wei, Dunlop, Malcolm, Houlston, Richard, and Peters, Ulrike
Abstract: Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies., Errata: Fernandez-Rozadilla, C., Timofeeva, M., Chen, Z. et al. Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries. Nat Genet (2023). DOI: 10.1038/s41588-023-01334-w
Published: 2023
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7. Prognostic role of detailed colorectal location and tumor molecular features : analyses of 13,101 colorectal cancer patients including 2994 early-onset cases

Author: Ugai, Tomotaka, Akimoto, Naohiko, Haruki, Koichiro, Harrison, Tabitha A., Cao, Yin, Qu, Conghui, Chan, Andrew T., Campbell, Peter T., Berndt, Sonja I., Buchanan, Daniel D., Cross, Amanda J., Diergaarde, Brenda, Gallinger, Steven J., Gunter, Marc J., Harlid, Sophia, Hidaka, Akihisa, Hoffmeister, Michael, Brenner, Hermann, Chang-Claude, Jenny, Hsu, Li, Jenkins, Mark A., Lin, Yi, Milne, Roger L., Moreno, Victor, Newcomb, Polly A., Nishihara, Reiko, Obon-Santacana, Mireia, Pai, Rish K., Sakoda, Lori C., Schoen, Robert E., Slattery, Martha L., Sun, Wei, Amitay, Efrat L., Alwers, Elizabeth, Thibodeau, Stephen N., Toland, Amanda E., van Guelpen, Bethany, Zaidi, Syed H., Potter, John D., Meyerhardt, Jeffrey A., Giannakis, Marios, Song, Mingyang, Nowak, Jonathan A., Peters, Ulrike, Phipps, Amanda I., Ogino, Shuji, Ugai, Tomotaka, Akimoto, Naohiko, Haruki, Koichiro, Harrison, Tabitha A., Cao, Yin, Qu, Conghui, Chan, Andrew T., Campbell, Peter T., Berndt, Sonja I., Buchanan, Daniel D., Cross, Amanda J., Diergaarde, Brenda, Gallinger, Steven J., Gunter, Marc J., Harlid, Sophia, Hidaka, Akihisa, Hoffmeister, Michael, Brenner, Hermann, Chang-Claude, Jenny, Hsu, Li, Jenkins, Mark A., Lin, Yi, Milne, Roger L., Moreno, Victor, Newcomb, Polly A., Nishihara, Reiko, Obon-Santacana, Mireia, Pai, Rish K., Sakoda, Lori C., Schoen, Robert E., Slattery, Martha L., Sun, Wei, Amitay, Efrat L., Alwers, Elizabeth, Thibodeau, Stephen N., Toland, Amanda E., van Guelpen, Bethany, Zaidi, Syed H., Potter, John D., Meyerhardt, Jeffrey A., Giannakis, Marios, Song, Mingyang, Nowak, Jonathan A., Peters, Ulrike, Phipps, Amanda I., and Ogino, Shuji
Abstract: Background: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics. Methods: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation. Results: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (Ptrend = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (Pinteraction = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [Ptrend < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70–0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI 1.15–3.92). The prognostic association of colon tumor location also differed by CIMP status (Pinteraction = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages. Conclusions: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.
Published: 2023
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8. 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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9. Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization

Author: King, Sontoria D., Veliginti, Swathi, Brouwers, Martijn C G J, Ren, Zhewen, Zheng, Wei, Setiawan, Veronica W., Wilkens, Lynne R., Shu, Xiao-Ou, Arslan, Alan A., Beane Freeman, Laura E., Bracci, Paige M., Canzian, Federico, Du, Mengmeng, Gallinger, Steven J., Giles, Graham G., Goodman, Phyllis J., Haiman, Christopher A., Kogevinas, Manolis, Kooperberg, Charles, LeMarchand, Loic, Neale, Rachel E., Visvanathan, Kala, White, Emily, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Berndt, Sonja I., Brais, Lauren K., Brennan, Paul, Buring, Julie E., Rabe, Kari G., Bamlet, William R., Chanock, Stephen J., Fuchs, Charles S., Gaziano, J Michael, Giovannucci, Edward L., Hackert, Thilo, Hassan, Manal M., Katzke, Verena, Kurtz, Robert C., Lee, I-Min, Malats, Núria, Murphy, Neil, Oberg, Ann L., Orlow, Irene, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Sesso, Howard D., Silverman, Debra T., Thompson, Ian M., Wactawski-Wende, Jean, Wang, Xiaoliang, Wentzensen, Nicolas, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Yu, Kai, Wolpin, Brian M., Duell, Eric J., Li, Donghui, Hung, Rayjean J., Perdomo, Sandra, McCullough, Marjorie L., Freedman, Neal D., Patel, Alpa V., Peters, Ulrike, Riboli, Elio, Sund, Malin, Tjønneland, Anne, Zhong, Jun, Van Den Eeden, Stephen K., Kraft, Peter, Risch, Harvey A., Amundadottir, Laufey T., Klein, Alison P., Stolzenberg-Solomon, Rachael Z., Antwi, Samuel O., King, Sontoria D., Veliginti, Swathi, Brouwers, Martijn C G J, Ren, Zhewen, Zheng, Wei, Setiawan, Veronica W., Wilkens, Lynne R., Shu, Xiao-Ou, Arslan, Alan A., Beane Freeman, Laura E., Bracci, Paige M., Canzian, Federico, Du, Mengmeng, Gallinger, Steven J., Giles, Graham G., Goodman, Phyllis J., Haiman, Christopher A., Kogevinas, Manolis, Kooperberg, Charles, LeMarchand, Loic, Neale, Rachel E., Visvanathan, Kala, White, Emily, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Berndt, Sonja I., Brais, Lauren K., Brennan, Paul, Buring, Julie E., Rabe, Kari G., Bamlet, William R., Chanock, Stephen J., Fuchs, Charles S., Gaziano, J Michael, Giovannucci, Edward L., Hackert, Thilo, Hassan, Manal M., Katzke, Verena, Kurtz, Robert C., Lee, I-Min, Malats, Núria, Murphy, Neil, Oberg, Ann L., Orlow, Irene, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Sesso, Howard D., Silverman, Debra T., Thompson, Ian M., Wactawski-Wende, Jean, Wang, Xiaoliang, Wentzensen, Nicolas, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Yu, Kai, Wolpin, Brian M., Duell, Eric J., Li, Donghui, Hung, Rayjean J., Perdomo, Sandra, McCullough, Marjorie L., Freedman, Neal D., Patel, Alpa V., Peters, Ulrike, Riboli, Elio, Sund, Malin, Tjønneland, Anne, Zhong, Jun, Van Den Eeden, Stephen K., Kraft, Peter, Risch, Harvey A., Amundadottir, Laufey T., Klein, Alison P., Stolzenberg-Solomon, Rachael Z., and Antwi, Samuel O.
Abstract: BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.
Published: 2023
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10. Validation of a genetic-enhanced risk prediction model for colorectal cancer in a large community-based cohort

Author: Su, Yu-Ru, Sakoda, Lori C., Jeon, Jihyoun, Thomas, Minta, Lin, Yi, Schneider, Jennifer L., Udaltsova, Natalia, Lee, Jeffrey K., Lansdorp-Vogelaar, Iris, Peterse, Elisabeth F P, Zauber, Ann G., Zheng, Jiayin, Zheng, Yingye, Hauser, Elizabeth, Baron, John A., Barry, Elizabeth L., Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D., Burnett-Hartman, Andrea, Campbell, Peter T., Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Figueiredo, Jane C., Gallinger, Steven J., Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Hua, Xinwei, Huyghe, Jeroen R., Jenkins, Mark A., Keku, Temitope O., Marchand, Loic Le, Li, Li, Lindblom, Annika, Moreno, Victor, Newcomb, Polly A., Pharoah, Paul D P, Platz, Elizabeth A., Potter, John D., Qu, Conghui, Rennert, Gad, Schoen, Robert E., Slattery, Martha L., Song, Mingyang, van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Vodicka, Pavel, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Hayes, Richard B., Peters, Ulrike, Corley, Douglas A., Hsu, Li, Su, Yu-Ru, Sakoda, Lori C., Jeon, Jihyoun, Thomas, Minta, Lin, Yi, Schneider, Jennifer L., Udaltsova, Natalia, Lee, Jeffrey K., Lansdorp-Vogelaar, Iris, Peterse, Elisabeth F P, Zauber, Ann G., Zheng, Jiayin, Zheng, Yingye, Hauser, Elizabeth, Baron, John A., Barry, Elizabeth L., Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D., Burnett-Hartman, Andrea, Campbell, Peter T., Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Figueiredo, Jane C., Gallinger, Steven J., Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Hua, Xinwei, Huyghe, Jeroen R., Jenkins, Mark A., Keku, Temitope O., Marchand, Loic Le, Li, Li, Lindblom, Annika, Moreno, Victor, Newcomb, Polly A., Pharoah, Paul D P, Platz, Elizabeth A., Potter, John D., Qu, Conghui, Rennert, Gad, Schoen, Robert E., Slattery, Martha L., Song, Mingyang, van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Vodicka, Pavel, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Hayes, Richard B., Peters, Ulrike, Corley, Douglas A., and Hsu, Li
Abstract: BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.
Published: 2023
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11. Molecular characteristics of early-onset colorectal cancer according to detailed anatomical locations : comparison with later-onset cases

Author: Ugai, Tomotaka, Haruki, Koichiro, Harrison, Tabitha A., Cao, Yin, Qu, Conghui, Chan, Andrew T., Campbell, Peter T., Akimoto, Naohiko, Berndt, Sonja, Brenner, Hermann, Buchanan, Daniel D., Chang-Claude, Jenny, Fujiyoshi, Kenji, Gallinger, Steven J., Gunter, Marc J., Hidaka, Akihisa, Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Milne, Roger L., Moreno, Victor, Newcomb, Polly A., Nishihara, Reiko, Pai, Rish K., Sakoda, Lori C., Slattery, Martha L., Sun, Wei, Amitay, Efrat L., Alwers, Elizabeth, Thibodeau, Stephen N., Toland, Amanda E., van Guelpen, Bethany, Woods, Michael O., Zaidi, Syed H., Potter, John D., Giannakis, Marios, Song, Mingyang, Nowak, Jonathan A., Phipps, Amanda I., Peters, Ulrike, Ogino, Shuji, Ugai, Tomotaka, Haruki, Koichiro, Harrison, Tabitha A., Cao, Yin, Qu, Conghui, Chan, Andrew T., Campbell, Peter T., Akimoto, Naohiko, Berndt, Sonja, Brenner, Hermann, Buchanan, Daniel D., Chang-Claude, Jenny, Fujiyoshi, Kenji, Gallinger, Steven J., Gunter, Marc J., Hidaka, Akihisa, Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Milne, Roger L., Moreno, Victor, Newcomb, Polly A., Nishihara, Reiko, Pai, Rish K., Sakoda, Lori C., Slattery, Martha L., Sun, Wei, Amitay, Efrat L., Alwers, Elizabeth, Thibodeau, Stephen N., Toland, Amanda E., van Guelpen, Bethany, Woods, Michael O., Zaidi, Syed H., Potter, John D., Giannakis, Marios, Song, Mingyang, Nowak, Jonathan A., Phipps, Amanda I., Peters, Ulrike, and Ogino, Shuji
Abstract: INTRODUCTION:Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management. METHODS:Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases. RESULTS:The proportions of MSI-high, CIMP-high, and BRAF-mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF-mutated) (all Ptrend<0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors (P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend<0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend. DISCUSSION:Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.
Published: 2023
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12. 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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13. 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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14. 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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15. Call to Improve the Quality of Prediction Tools for Intrahepatic Cholangiocarcinoma Resection:A Critical Appraisal, Systematic Review, and External Validation Study

Author: Choi, Woo Jin, Walker, Richard, Rajendran, Luckshi, Jones, Owen, Gravely, Annie, Englesakis, Marina, Gallinger, Steven, Hirschfield, Gideon, Hansen, Bettina, Sapisochin, Gonzalo, Choi, Woo Jin, Walker, Richard, Rajendran, Luckshi, Jones, Owen, Gravely, Annie, Englesakis, Marina, Gallinger, Steven, Hirschfield, Gideon, Hansen, Bettina, and Sapisochin, Gonzalo
Abstract: OBJECTIVE: To conduct a systematic review, critical appraisal, and external validation of survival prediction tools for patients undergoing intrahepatic cholangiocarcinoma (iCCA) resection.SUMMARY BACKGROUND DATA: Despite the development of several survival prediction tools in recent years for patients undergoing iCCA resections, there is a lack of critical appraisal and external validation of these models.METHODS: We conducted a systematic review and critical appraisal of survival and recurrence prediction models for patients undergoing curative-intent iCCA resections. Studies were evaluated based on their model design, risk of bias, reporting, performance, and validation results. We identified the best model and externally validated it using our institution's data.RESULTS: This review included a total of 31 studies, consisting of 26 studies with original prediction tools and 5 studies that only conducted external validations. Among the 26, 54% of the studies conducted internal validations, 46% conducted external validations, and only 1 study scored a low risk of bias. Harrell's C-statistics ranged from 0.67 to 0.76 for internal validation and from 0.64 to 0.75 for external validation. Only 81% of the studies reported model calibration. Our external validation of the best model (Intrahepatic Cholangiocarcinoma [ICC]-Metroticket) estimated Harrell's and Uno's C-statistics of 0.67 (95% CI: 0.56-0.77) and Uno's time-dependent area under the receiver operating characteristic curve (AUC) of 0.71 (95% CI: 0.53-0.88), with a Brier score of 0.20 (95% CI: 0.15-0.26) and good calibration plots.CONCLUSIONS: Many prediction models have been published in recent years, but their quality remains poor, and minimal methodological quality improvement has been observed. The ICC-Metroticket was selected as the best model (Uno's time-dependent AUC of 0.71) for 5-year overall survival prediction in patients undergoing curative-intent iCCA resection.
Published: 2023

16. Preoperative neutrophil-to-lymphocyte ratio is prognostic for early recurrence after curative intrahepatic cholangiocarcinoma resection

Author: Choi, Woo Jin, Murillo Perez, Fiorella, Gravely, Annabel, Ivanics, Tommy, Claasen, Marco P. A. W., Abraham, Liza, Abreu, Phillipe, Visser, Robin, Gallinger, Steven, Hansen, Bettina E., Sapisochin, Gonzalo, Choi, Woo Jin, Murillo Perez, Fiorella, Gravely, Annabel, Ivanics, Tommy, Claasen, Marco P. A. W., Abraham, Liza, Abreu, Phillipe, Visser, Robin, Gallinger, Steven, Hansen, Bettina E., and Sapisochin, Gonzalo
Abstract: Backgrounds/Aims: Within two years of surgery, 70% of resected intrahepatic cholangiocarcinoma (iCCA) recur. Better biomarkers are needed to identify those at risk of “early recurrence” (ER). In this study, we defined ER and investigated whether preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic-inflammatory index were prognostic of both overall relapse and ER after curative hepatectomy for iCCA. Methods: A retrospective cohort of patients who underwent curative-intent hepatectomy for iCCA between 2005 and 2017 were created. The cut-off timepoint for the ER of iCCA was estimated using a piecewise linear regression model. Univariable analyses of recurrence were conducted for the overall, early, and late recurrence periods. For the early and late recurrence periods, multivariable Cox regression with time-varying regression coefficient analysis was used. Results: A total of 113 patients were included in this study. ER was defined as recurrence within 12 months of a curative resection. Among the included patients, 38.1% experienced ER. In the univariable model, a higher preoperative NLR (> 4.3) was significantly associated with an increased risk of recurrence overall and in the first 12 months after curative surgery. In the multivariable model, a higher NLR was associated with a higher recurrence rate overall and in the ER period (≤ 12 months), but not in the late recurrence period. Conclusions: Preoperative NLR was prognostic of both overall recurrence and ER after curative iCCA resection. NLR is easily obtained before and after surgery and should be integrated into ER prediction tools to guide preoperative treatments and intensify postoperative follow-up.
Published: 2023
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17. Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes

Author: Mahmood, Khalid, Thomas, Minta, Qu, Conghui, Wang, Xiaoliang, Huyghe, Jeroen R., Joo, Jihoon E., Georgeson, Peter, Arndt, Volker, Berndt, Sonja I., Bézieau, Stéphane, Bien, Stephanie A., Bishop, D.T., Brenner, Hermann, Brezina, Stefanie, Burnett-Hartman, Andrea, Campbell, Peter T., Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Cremolini, Chiara, Diergaarde, Brenda, Figueiredo, Jane C., FitzGerald, Liesel M., Gago-Dominguez, Manuela, Gallinger, Steven, Giles, Graham G., Gsu, Andrea, Gunter, Marc J., Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lenz, Heinz Josef, Li, Christopher I., Li, Li, Lin, Yi, Lindblom, Annika, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, van Duijnhoven, Franzel J.B., Hsu, Li, Buchanan, Daniel D., Peters, Ulrike, Mahmood, Khalid, Thomas, Minta, Qu, Conghui, Wang, Xiaoliang, Huyghe, Jeroen R., Joo, Jihoon E., Georgeson, Peter, Arndt, Volker, Berndt, Sonja I., Bézieau, Stéphane, Bien, Stephanie A., Bishop, D.T., Brenner, Hermann, Brezina, Stefanie, Burnett-Hartman, Andrea, Campbell, Peter T., Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Cremolini, Chiara, Diergaarde, Brenda, Figueiredo, Jane C., FitzGerald, Liesel M., Gago-Dominguez, Manuela, Gallinger, Steven, Giles, Graham G., Gsu, Andrea, Gunter, Marc J., Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Keku, Temitope O., Kundaje, Anshul, Le Marchand, Loic, Lenz, Heinz Josef, Li, Christopher I., Li, Li, Lin, Yi, Lindblom, Annika, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Newton, Christina C., Obón-Santacana, Mireia, Ogino, Shuji, van Duijnhoven, Franzel J.B., Hsu, Li, Buchanan, Daniel D., and Peters, Ulrike
Published: 2023

18. Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses

Author: Dimou, Niki, Kim, Andre E., Flanagan, Orlagh, Murphy, Neil, Diez-Obrero, Virginia, Shcherbina, Anna, Aglago, Elom K., Bouras, Emmanouil, Campbell, Peter T., Casey, Graham, Gallinger, Steven, Gruber, Stephen B., Jenkins, Mark A., Lin, Yi, Moreno, Victor, Ruiz-Narvaez, Edward, Stern, Mariana C., Tian, Yu, Tsilidis, Kostas K., Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bézieau, Stéphane, Bien, Stephanie A., Bishop, D.T., Brenner, Hermann, Budiarto, Arif, Carreras-Torres, Robert, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chanock, Stephen J., Chen, Xuechen, Conti, David V., Dampier, Christopher H., Devall, Matthew, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gsur, Andrea, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jordahl, Kristina, Kawaguchi, Eric, Keku, Temitope O., Larsson, Susanna C., Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Mahesworo, Bharuno, Morrison, John, Newcomb, Polly A., Newton, Christina C., Obon-Santacana, Mireia, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Pharoah, Paul D.P., Platz, Elizabeth A., Potter, John D., Rennert, Gad, Scacheri, Peter C., Schoen, Robert E., Su, Yu Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Franzel J.B., Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, White, Emily, Wolk, Alicja, Woods, Michael O., Qu, Conghui, Kundaje, Anshul, Hsu, Li, Gauderman, W.J., Gunter, Marc J., Peters, Ulrike, Dimou, Niki, Kim, Andre E., Flanagan, Orlagh, Murphy, Neil, Diez-Obrero, Virginia, Shcherbina, Anna, Aglago, Elom K., Bouras, Emmanouil, Campbell, Peter T., Casey, Graham, Gallinger, Steven, Gruber, Stephen B., Jenkins, Mark A., Lin, Yi, Moreno, Victor, Ruiz-Narvaez, Edward, Stern, Mariana C., Tian, Yu, Tsilidis, Kostas K., Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bézieau, Stéphane, Bien, Stephanie A., Bishop, D.T., Brenner, Hermann, Budiarto, Arif, Carreras-Torres, Robert, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chanock, Stephen J., Chen, Xuechen, Conti, David V., Dampier, Christopher H., Devall, Matthew, Drew, David A., Figueiredo, Jane C., Giles, Graham G., Gsur, Andrea, Harrison, Tabitha A., Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen R., Jordahl, Kristina, Kawaguchi, Eric, Keku, Temitope O., Larsson, Susanna C., Le Marchand, Loic, Lewinger, Juan Pablo, Li, Li, Mahesworo, Bharuno, Morrison, John, Newcomb, Polly A., Newton, Christina C., Obon-Santacana, Mireia, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Pharoah, Paul D.P., Platz, Elizabeth A., Potter, John D., Rennert, Gad, Scacheri, Peter C., Schoen, Robert E., Su, Yu Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Ulrich, Cornelia M., Um, Caroline Y., van Duijnhoven, Franzel J.B., Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, White, Emily, Wolk, Alicja, Woods, Michael O., Qu, Conghui, Kundaje, Anshul, Hsu, Li, Gauderman, W.J., Gunter, Marc J., and Peters, Ulrike
Abstract: Background: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. Methods: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). Results: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 – ORAA: 1.62, 95% CI: 1.34–1.96; ORAG: 1.41, 95% CI: 1.30–1.54; ORGG: 1.22, 95% CI: 1.13–1.31; p-value3-d.f.: 5.46 × 10−11) and 13q14.13 (rs9526201, LRCH1 – ORGG: 2.11, 95% CI: 1.56–2.83; ORGA: 1.52, 95% CI: 1.38–1.68; ORAA: 1.13, 95% CI: 1.06–1.21; p-value2-d.f.: 7.84 × 10−09). Discussion: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.
Published: 2023

19. 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.T., 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 J.B., 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.J., 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.T., 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 J.B., 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.J., 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

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

Author: Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W. James, Peters, Ulrike, Tsilidis, Konstantinos K., Campbell, Peter T., Aglago, Elom K., Kim, Andre, Lin, Yi, Qu, Conghui, Evangelou, Marina, Ren, Yu, Morrison, John, Albanes, Demetrius, Arndt, Volker, Barry, Elizabeth L., Baurley, James W., Berndt, Sonja I., Bien, Stephanie A., Bishop, D. Timothy, Bouras, Emmanouil, Brenner, Hermann, Buchanan, Daniel D., Budiarto, Arif, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng Wawan, Chan, Andrew T., Chang-Claude, Jenny, Chen, Xuechen, Conti, David V., Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane C., Gallinger, Steven, Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampel, Heather, Harlid, Sophia, Hidaka, Akihisa, Harrison, Tabitha A., Hoffmeister, Michael, Huyghe, Jeroen R., Jenkins, Mark A., Jordahl, Kristina, Joshi, Amit D., Kawaguchi, Eric S., Keku, Temitope O., Kundaje, Anshul, Larsson, Susanna C., Marchand, Loic Le, Lewinger, Juan Pablo, Li, Li, Lynch, Brigid M., Mahesworo, Bharuno, Mandic, Marko, Obón-Santacana, Mireia, Moreno, Victor, Murphy, Neil, Nan, Hongmei, Nassir, Rami, Newcomb, Polly A., Ogino, Shuji, Ose, Jennifer, Pai, Rish K., Palmer, Julie R., Papadimitriou, Nikos, Pardamean, Bens, Peoples, Anita R., Platz, Elizabeth A., Potter, John D., Prentice, Ross L., Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori C., Scacheri, Peter C., Schmit, Stephanie L., Schoen, Robert E., Shcherbina, Anna, Slattery, Martha L., Stern, Mariana C., Su, Yu Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Tian, Yu, Ulrich, Cornelia M., van Duijnhoven, Franzel Jb, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zemlianskaia, Natalia, Hsu, Li, Gauderman, W. James, Peters, Ulrike, Tsilidis, Konstantinos K., and Campbell, Peter T.
Abstract: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. 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

21. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment:a report from the prospective Lynch syndrome database

Author: Dominguez-Valentin, Mev, Haupt, Saskia, Seppälä, Toni T., Sampson, Julian R., Sunde, Lone, Bernstein, Inge, Jenkins, Mark A., Engel, Christoph, Aretz, Stefan, Nielsen, Maartje, Capella, Gabriel, Balaguer, Francesc, Evans, Dafydd Gareth, Burn, John, Holinski-Feder, Elke, Bertario, Lucio, Bonanni, Bernardo, Lindblom, Annika, Levi, Zohar, Macrae, Finlay, Winship, Ingrid, Plazzer, John Paul, Sijmons, Rolf, Laghi, Luigi, Della Valle, Adriana, Heinimann, Karl, Dębniak, Tadeusz, Fruscio, Robert, Lopez-Koestner, Francisco, Alvarez-Valenzuela, Karin, Katz, Lior H., Laish, Ido, Vainer, Elez, Vaccaro, Carlos, Carraro, Dirce Maria, Monahan, Kevin, Half, Elizabeth, Stakelum, Aine, Winter, Des, Kennelly, Rory, Gluck, Nathan, Sheth, Harsh, Abu-Freha, Naim, Greenblatt, Marc, Rossi, Benedito Mauro, Bohorquez, Mabel, Cavestro, Giulia Martina, Lino-Silva, Leonardo S., Horisberger, Karoline, Tibiletti, Maria Grazia, Nascimento, Ivana do, Thomas, Huw, Rossi, Norma Teresa, Apolinário da Silva, Leandro, Zaránd, Attila, Ruiz-Bañobre, Juan, Heuveline, Vincent, Mecklin, Jukka Pekka, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Lepistö, Anna, Peltomäki, Päivi, Therkildsen, Christina, Madsen, Mia Gebauer, Burgdorf, Stefan Kobbelgaard, Hopper, John L., Win, Aung Ko, Haile, Robert W., Lindor, Noralane, Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane, Buchanan, Daniel D., Thibodeau, Stephen N., von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Schröck, Evelin, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Hüneburg, Robert, Redler, Silke, Büttner, Reinhard, Weitz, Jürgen, Pineda, Marta, Duenas, Nuria, Vidal, Joan Brunet, Moreira, Leticia, Sánchez, Ariadna, Hovig, Eivind, Nakken, Sigve, Green, Kate, Lalloo, Fiona, Hill, James, Crosbie, Emma, Mints, Miriam, Goldberg, Yael, Tjandra, Douglas, ten Broeke, Sanne W., Kariv, Revital, Rosner, Guy, Advani, Suresh H., Thomas, Lidiya, Shah, Pankaj, Shah, Mithun, Neffa, Florencia, Esperon, Patricia, Pavicic, Walter, Torrezan, Giovana Tardin, Bassaneze, Thiago, Martin, Claudia Alejandra, Moslein, Gabriela, Moller, Pål, Dominguez-Valentin, Mev, Haupt, Saskia, Seppälä, Toni T., Sampson, Julian R., Sunde, Lone, Bernstein, Inge, Jenkins, Mark A., Engel, Christoph, Aretz, Stefan, Nielsen, Maartje, Capella, Gabriel, Balaguer, Francesc, Evans, Dafydd Gareth, Burn, John, Holinski-Feder, Elke, Bertario, Lucio, Bonanni, Bernardo, Lindblom, Annika, Levi, Zohar, Macrae, Finlay, Winship, Ingrid, Plazzer, John Paul, Sijmons, Rolf, Laghi, Luigi, Della Valle, Adriana, Heinimann, Karl, Dębniak, Tadeusz, Fruscio, Robert, Lopez-Koestner, Francisco, Alvarez-Valenzuela, Karin, Katz, Lior H., Laish, Ido, Vainer, Elez, Vaccaro, Carlos, Carraro, Dirce Maria, Monahan, Kevin, Half, Elizabeth, Stakelum, Aine, Winter, Des, Kennelly, Rory, Gluck, Nathan, Sheth, Harsh, Abu-Freha, Naim, Greenblatt, Marc, Rossi, Benedito Mauro, Bohorquez, Mabel, Cavestro, Giulia Martina, Lino-Silva, Leonardo S., Horisberger, Karoline, Tibiletti, Maria Grazia, Nascimento, Ivana do, Thomas, Huw, Rossi, Norma Teresa, Apolinário da Silva, Leandro, Zaránd, Attila, Ruiz-Bañobre, Juan, Heuveline, Vincent, Mecklin, Jukka Pekka, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Lepistö, Anna, Peltomäki, Päivi, Therkildsen, Christina, Madsen, Mia Gebauer, Burgdorf, Stefan Kobbelgaard, Hopper, John L., Win, Aung Ko, Haile, Robert W., Lindor, Noralane, Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane, Buchanan, Daniel D., Thibodeau, Stephen N., von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Schröck, Evelin, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Hüneburg, Robert, Redler, Silke, Büttner, Reinhard, Weitz, Jürgen, Pineda, Marta, Duenas, Nuria, Vidal, Joan Brunet, Moreira, Leticia, Sánchez, Ariadna, Hovig, Eivind, Nakken, Sigve, Green, Kate, Lalloo, Fiona, Hill, James, Crosbie, Emma, Mints, Miriam, Goldberg, Yael, Tjandra, Douglas, ten Broeke, Sanne W., Kariv, Revital, Rosner, Guy, Advani, Suresh H., Thomas, Lidiya, Shah, Pankaj, Shah, Mithun, Neffa, Florencia, Esperon, Patricia, Pavicic, Walter, Torrezan, Giovana Tardin, Bassaneze, Thiago, Martin, Claudia Alejandra, Moslein, Gabriela, and Moller, Pål
Abstract: Background The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical ca, Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We ac
Published: 2023

22. Author Correction : Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author: Fernandez-Rozadilla, Ceres, Timofeeva, Maria, Chen, Zhishan, Law, Philip, Thomas, Minta, Schmit, Stephanie, Díez-Obrero, Virginia, Hsu, Li, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah, Svinti, Victoria, Donnelly, Kevin, Farrington, Susan, Blackmur, James, Vaughan-Shaw, Peter, Shu, Xiao Ou, Long, Jirong, Cai, Qiuyin, Guo, Xingyi, Lu, Yingchang, Broderick, Peter, Studd, James, Huyghe, Jeroen, Harrison, Tabitha, Conti, David, Dampier, Christopher, Devall, Mathew, Schumacher, Fredrick, Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Moratalla-Navarro, Ferran, 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, Jenkins, Mark, Win, Aung Ko, Pai, Rish, Figueiredo, Jane, Haile, Robert, Gallinger, Steven, Woods, Michael, Newcomb, Polly, Duggan, David, Cheadle, Jeremy, Kaplan, Richard, Maughan, Timothy, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Lukka Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri, Rissanen, Harri, Pukkala, Eero, Eriksson, Johan, Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Zanke, Brent, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie, Ruiz-Narvaez, Edward, Palmer, Julie, Buchanan, Daniel, Platz, Elizabeth, Visvanathan, Kala, Ulrich, Cornelia, Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter, Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha, Potter, John, Tsilidis, Konstantinos, Schulze, Matthias, Gunter, Marc, Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Stern, Mariana, Pardamean, Bens, Bishop, Timothy, Giles, Graham, Southey, Melissa, Idos, Gregory, McDonnell, Kevin, Abu-Ful, Zomoroda, Greenson, Joel, Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu Ru, Steinfelder, Robert, Keku, Temitope, van Guelpen, Bethany, Hudson, Thomas, Hampel, Heather, Pearlman, Rachel, Berndt, Sonja, Hayes, Richard, Martinez, Marie Elena, Thomas, Sushma, Corley, Douglas, Pharoah, Paul, Larsson, Susanna, Yen, Yun, Lenz, Heinz Josef, White, Emily, Li, Li, Doheny, Kimberly, Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew, Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David, Joshi, Amit, Schafmayer, Clemens, Scacheri, Peter, Kundaje, Anshul, Nickerson, Deborah, Schoen, Robert, Hampe, Jochen, Stadler, Zsofia, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Papadopoulos, Nickolas, Edlund, Chistopher, Gauderman, William, Thomas, Duncan, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen, van Duijnhoven, Franzel, Feskens, Edith, Sakoda, Lori, Gago-Dominguez, Manuela, Wolk, Alicja, Naccarati, Alessio, Pardini, Barbara, FitzGerald, Liesel, Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie, Kooperberg, Charles, Li, Christopher, Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Tangen, Catherine, Mardis, Elaine, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Haiman, Christopher, Le Marchand, Loic, Wu, Anna, Qu, Chenxu, McNeil, Caroline, Coetzee, Gerhard, Hayward, Caroline, Deary, Ian, Harris, Sarah, Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Moreno, Victor, Casey, Graham, Gruber, Stephen, Tomlinson, Ian, Zheng, Wei, Dunlop, Malcolm, Houlston, Richard, Peters, Ulrike, Fernandez-Rozadilla, Ceres, Timofeeva, Maria, Chen, Zhishan, Law, Philip, Thomas, Minta, Schmit, Stephanie, Díez-Obrero, Virginia, Hsu, Li, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah, Svinti, Victoria, Donnelly, Kevin, Farrington, Susan, Blackmur, James, Vaughan-Shaw, Peter, Shu, Xiao Ou, Long, Jirong, Cai, Qiuyin, Guo, Xingyi, Lu, Yingchang, Broderick, Peter, Studd, James, Huyghe, Jeroen, Harrison, Tabitha, Conti, David, Dampier, Christopher, Devall, Mathew, Schumacher, Fredrick, Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Moratalla-Navarro, Ferran, 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, Jenkins, Mark, Win, Aung Ko, Pai, Rish, Figueiredo, Jane, Haile, Robert, Gallinger, Steven, Woods, Michael, Newcomb, Polly, Duggan, David, Cheadle, Jeremy, Kaplan, Richard, Maughan, Timothy, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Lukka Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri, Rissanen, Harri, Pukkala, Eero, Eriksson, Johan, Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Zanke, Brent, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie, Ruiz-Narvaez, Edward, Palmer, Julie, Buchanan, Daniel, Platz, Elizabeth, Visvanathan, Kala, Ulrich, Cornelia, Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter, Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha, Potter, John, Tsilidis, Konstantinos, Schulze, Matthias, Gunter, Marc, Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Stern, Mariana, Pardamean, Bens, Bishop, Timothy, Giles, Graham, Southey, Melissa, Idos, Gregory, McDonnell, Kevin, Abu-Ful, Zomoroda, Greenson, Joel, Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu Ru, Steinfelder, Robert, Keku, Temitope, van Guelpen, Bethany, Hudson, Thomas, Hampel, Heather, Pearlman, Rachel, Berndt, Sonja, Hayes, Richard, Martinez, Marie Elena, Thomas, Sushma, Corley, Douglas, Pharoah, Paul, Larsson, Susanna, Yen, Yun, Lenz, Heinz Josef, White, Emily, Li, Li, Doheny, Kimberly, Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew, Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David, Joshi, Amit, Schafmayer, Clemens, Scacheri, Peter, Kundaje, Anshul, Nickerson, Deborah, Schoen, Robert, Hampe, Jochen, Stadler, Zsofia, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Papadopoulos, Nickolas, Edlund, Chistopher, Gauderman, William, Thomas, Duncan, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen, van Duijnhoven, Franzel, Feskens, Edith, Sakoda, Lori, Gago-Dominguez, Manuela, Wolk, Alicja, Naccarati, Alessio, Pardini, Barbara, FitzGerald, Liesel, Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie, Kooperberg, Charles, Li, Christopher, Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Tangen, Catherine, Mardis, Elaine, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Haiman, Christopher, Le Marchand, Loic, Wu, Anna, Qu, Chenxu, McNeil, Caroline, Coetzee, Gerhard, Hayward, Caroline, Deary, Ian, Harris, Sarah, Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Moreno, Victor, Casey, Graham, Gruber, Stephen, Tomlinson, Ian, Zheng, Wei, Dunlop, Malcolm, Houlston, Richard, and Peters, Ulrike
Abstract: In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article.
Published: 2023

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
Full Text: View/download PDF

24. 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

25. Preoperative neutrophil-to-lymphocyte ratio is prognostic for early recurrence after curative intrahepatic cholangiocarcinoma resection

Author: Jin Choi, Woo, Murillo Perez, Fiorella, Gravely, Annabel, Ivanics, Tommy, Claasen, Marco P.A.W., Abraham, Liza, Abreu, Phillipe, Visser, Robin, Gallinger, Steven, Hansen, Bettina E., Sapisochin, Gonzalo, Jin Choi, Woo, Murillo Perez, Fiorella, Gravely, Annabel, Ivanics, Tommy, Claasen, Marco P.A.W., Abraham, Liza, Abreu, Phillipe, Visser, Robin, Gallinger, Steven, Hansen, Bettina E., and Sapisochin, Gonzalo
Abstract: Backgrounds/Aims: Within two years of surgery, 70% of resected intrahepatic cholangiocarcinoma (iCCA) recur. Better biomarkers are needed to identify those at risk of “early recurrence” (ER). In this study, we defined ER and investigated whether preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic-inflammatory index were prognostic of both overall relapse and ER after curative hepatectomy for iCCA. Methods: A retrospective cohort of patients who underwent curative-intent hepatectomy for iCCA between 2005 and 2017 were created. The cut-off timepoint for the ER of iCCA was estimated using a piecewise linear regression model. Univariable analyses of recurrence were conducted for the overall, early, and late recurrence periods. For the early and late recurrence periods, multivariable Cox regression with time-varying regression coefficient analysis was used. Results: A total of 113 patients were included in this study. ER was defined as recurrence within 12 months of a curative resection. Among the included patients, 38.1% experienced ER. In the univariable model, a higher preoperative NLR (> 4.3) was significantly associated with an increased risk of recurrence overall and in the first 12 months after curative surgery. In the multivariable model, a higher NLR was associated with a higher recurrence rate overall and in the ER period (≤ 12 months), but not in the late recurrence period. Conclusions: Preoperative NLR was prognostic of both overall recurrence and ER after curative iCCA resection. NLR is easily obtained before and after surgery and should be integrated into ER prediction tools to guide preoperative treatments and intensify postoperative follow-up.
Published: 2023

26. 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.T., 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.J., 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.T., 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.J.
Abstract: 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

27. Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort

Author: Su, Yu Ru, Sakoda, Lori C., Jeon, Jihyoun, Thomas, Minta, Lin, Yi, Schneider, Jennifer L., Udaltsova, Natalia, Lee, Jeffrey K., Lansdorp-Vogelaar, Iris, Peterse, Elisabeth F.P., Zauber, Ann G., Zheng, Jiayin, Zheng, Yingye, Hauser, Elizabeth, Baron, John A., Barry, Elizabeth L., Bishop, D.T., Brenner, Hermann, Buchanan, Daniel D., Burnett-Hartman, Andrea, Campbell, Peter T., Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Figueiredo, Jane C., Gallinger, Steven J., Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Hua, Xinwei, Huyghe, Jeroen R., Jenkins, Mark A., Keku, Temitope O., Marchand, Loic Le, Li, Li, Lindblom, Annika, Moreno, Victor, Newcomb, Polly A., Pharoah, Paul D.P., Platz, Elizabeth A., Potter, John D., Qu, Conghui, Rennert, Gad, Schoen, Robert E., Slattery, Martha L., Song, Mingyang, van Duijnhoven, Fränzel J.B., Van Guelpen, Bethany, Vodicka, Pavel, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Hayes, Richard B., Peters, Ulrike, Corley, Douglas A., Hsu, Li, Su, Yu Ru, Sakoda, Lori C., Jeon, Jihyoun, Thomas, Minta, Lin, Yi, Schneider, Jennifer L., Udaltsova, Natalia, Lee, Jeffrey K., Lansdorp-Vogelaar, Iris, Peterse, Elisabeth F.P., Zauber, Ann G., Zheng, Jiayin, Zheng, Yingye, Hauser, Elizabeth, Baron, John A., Barry, Elizabeth L., Bishop, D.T., Brenner, Hermann, Buchanan, Daniel D., Burnett-Hartman, Andrea, Campbell, Peter T., Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Figueiredo, Jane C., Gallinger, Steven J., Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Gunter, Marc J., Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Hua, Xinwei, Huyghe, Jeroen R., Jenkins, Mark A., Keku, Temitope O., Marchand, Loic Le, Li, Li, Lindblom, Annika, Moreno, Victor, Newcomb, Polly A., Pharoah, Paul D.P., Platz, Elizabeth A., Potter, John D., Qu, Conghui, Rennert, Gad, Schoen, Robert E., Slattery, Martha L., Song, Mingyang, van Duijnhoven, Fränzel J.B., Van Guelpen, Bethany, Vodicka, Pavel, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Hayes, Richard B., Peters, Ulrike, Corley, Douglas A., and Hsu, Li
Abstract: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.
Published: 2023

28. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment:a report from the prospective Lynch syndrome database

Author: Dominguez-Valentin, Mev, Haupt, Saskia, Seppälä, Toni T., Sampson, Julian R., Sunde, Lone, Bernstein, Inge, Jenkins, Mark A., Engel, Christoph, Aretz, Stefan, Nielsen, Maartje, Capella, Gabriel, Balaguer, Francesc, Evans, Dafydd Gareth, Burn, John, Holinski-Feder, Elke, Bertario, Lucio, Bonanni, Bernardo, Lindblom, Annika, Levi, Zohar, Macrae, Finlay, Winship, Ingrid, Plazzer, John Paul, Sijmons, Rolf, Laghi, Luigi, Della Valle, Adriana, Heinimann, Karl, Dębniak, Tadeusz, Fruscio, Robert, Lopez-Koestner, Francisco, Alvarez-Valenzuela, Karin, Katz, Lior H., Laish, Ido, Vainer, Elez, Vaccaro, Carlos, Carraro, Dirce Maria, Monahan, Kevin, Half, Elizabeth, Stakelum, Aine, Winter, Des, Kennelly, Rory, Gluck, Nathan, Sheth, Harsh, Abu-Freha, Naim, Greenblatt, Marc, Rossi, Benedito Mauro, Bohorquez, Mabel, Cavestro, Giulia Martina, Lino-Silva, Leonardo S., Horisberger, Karoline, Tibiletti, Maria Grazia, Nascimento, Ivana do, Thomas, Huw, Rossi, Norma Teresa, Apolinário da Silva, Leandro, Zaránd, Attila, Ruiz-Bañobre, Juan, Heuveline, Vincent, Mecklin, Jukka Pekka, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Lepistö, Anna, Peltomäki, Päivi, Therkildsen, Christina, Madsen, Mia Gebauer, Burgdorf, Stefan Kobbelgaard, Hopper, John L., Win, Aung Ko, Haile, Robert W., Lindor, Noralane, Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane, Buchanan, Daniel D., Thibodeau, Stephen N., von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Schröck, Evelin, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Hüneburg, Robert, Redler, Silke, Büttner, Reinhard, Weitz, Jürgen, Pineda, Marta, Duenas, Nuria, Vidal, Joan Brunet, Moreira, Leticia, Sánchez, Ariadna, Hovig, Eivind, Nakken, Sigve, Green, Kate, Lalloo, Fiona, Hill, James, Crosbie, Emma, Mints, Miriam, Goldberg, Yael, Tjandra, Douglas, ten Broeke, Sanne W., Kariv, Revital, Rosner, Guy, Advani, Suresh H., Thomas, Lidiya, Shah, Pankaj, Shah, Mithun, Neffa, Florencia, Esperon, Patricia, Pavicic, Walter, Torrezan, Giovana Tardin, Bassaneze, Thiago, Martin, Claudia Alejandra, Moslein, Gabriela, Moller, Pål, Dominguez-Valentin, Mev, Haupt, Saskia, Seppälä, Toni T., Sampson, Julian R., Sunde, Lone, Bernstein, Inge, Jenkins, Mark A., Engel, Christoph, Aretz, Stefan, Nielsen, Maartje, Capella, Gabriel, Balaguer, Francesc, Evans, Dafydd Gareth, Burn, John, Holinski-Feder, Elke, Bertario, Lucio, Bonanni, Bernardo, Lindblom, Annika, Levi, Zohar, Macrae, Finlay, Winship, Ingrid, Plazzer, John Paul, Sijmons, Rolf, Laghi, Luigi, Della Valle, Adriana, Heinimann, Karl, Dębniak, Tadeusz, Fruscio, Robert, Lopez-Koestner, Francisco, Alvarez-Valenzuela, Karin, Katz, Lior H., Laish, Ido, Vainer, Elez, Vaccaro, Carlos, Carraro, Dirce Maria, Monahan, Kevin, Half, Elizabeth, Stakelum, Aine, Winter, Des, Kennelly, Rory, Gluck, Nathan, Sheth, Harsh, Abu-Freha, Naim, Greenblatt, Marc, Rossi, Benedito Mauro, Bohorquez, Mabel, Cavestro, Giulia Martina, Lino-Silva, Leonardo S., Horisberger, Karoline, Tibiletti, Maria Grazia, Nascimento, Ivana do, Thomas, Huw, Rossi, Norma Teresa, Apolinário da Silva, Leandro, Zaránd, Attila, Ruiz-Bañobre, Juan, Heuveline, Vincent, Mecklin, Jukka Pekka, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Lepistö, Anna, Peltomäki, Päivi, Therkildsen, Christina, Madsen, Mia Gebauer, Burgdorf, Stefan Kobbelgaard, Hopper, John L., Win, Aung Ko, Haile, Robert W., Lindor, Noralane, Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane, Buchanan, Daniel D., Thibodeau, Stephen N., von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Schröck, Evelin, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Hüneburg, Robert, Redler, Silke, Büttner, Reinhard, Weitz, Jürgen, Pineda, Marta, Duenas, Nuria, Vidal, Joan Brunet, Moreira, Leticia, Sánchez, Ariadna, Hovig, Eivind, Nakken, Sigve, Green, Kate, Lalloo, Fiona, Hill, James, Crosbie, Emma, Mints, Miriam, Goldberg, Yael, Tjandra, Douglas, ten Broeke, Sanne W., Kariv, Revital, Rosner, Guy, Advani, Suresh H., Thomas, Lidiya, Shah, Pankaj, Shah, Mithun, Neffa, Florencia, Esperon, Patricia, Pavicic, Walter, Torrezan, Giovana Tardin, Bassaneze, Thiago, Martin, Claudia Alejandra, Moslein, Gabriela, and Moller, Pål
Abstract: Background The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical ca, Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We ac
Published: 2023

29. 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

30. ASO Visual Abstract: Systematic Review and Meta-analysis of Prognostic Factors for Early Recurrence in Intrahepatic Cholangiocarcinoma After Curative-Intent Resection

Author: Choi, Woo Jin, Williams, Phil J., Claasen, Marco P. A. W., Ivanics, Tommy, Englesakis, Marina, Gallinger, Steven, Hansen, Bettina, Sapisochin, Gonzalo, Choi, Woo Jin, Williams, Phil J., Claasen, Marco P. A. W., Ivanics, Tommy, Englesakis, Marina, Gallinger, Steven, Hansen, Bettina, and Sapisochin, Gonzalo
Published: 2022
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31. Systematic Review and Meta-Analysis of Prognostic Factors for Early Recurrence in Intrahepatic Cholangiocarcinoma After Curative-Intent Resection

Author: Choi, Woo Jin, Williams, Phil J., Claasen, Marco P. A. W., Ivanics, Tommy, Englesakis, Marina, Gallinger, Steven, Hansen, Bettina, Sapisochin, Gonzalo, Choi, Woo Jin, Williams, Phil J., Claasen, Marco P. A. W., Ivanics, Tommy, Englesakis, Marina, Gallinger, Steven, Hansen, Bettina, and Sapisochin, Gonzalo
Published: 2022
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32. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

Author: Mullins, Niamh, Mullins, Niamh, Kang, JooEun, Campos, Adrian I, Coleman, Jonathan RI, Edwards, Alexis C, Galfalvy, Hanga, Levey, Daniel F, Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J, Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D, Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B, Bergen, Andrew W, Berrettini, Wade H, Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J, Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M, Gallinger, Steven, Glatt, Stephen J, Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A, Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Keel, Pamela K, Kennedy, James L, Klump, Kelly L, Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J, Marshall, Christian R, Mitchell, James E, Monson, Eric T, Myers, Richard M, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W, Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M, Treasure, Janet, Tsuang, Ming T, Witt, Stephanie H, Woodside, D Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M, Alda, Martin, Alfredsson, Lars, Andreassen, Ole A, Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M Helena, Bass, Nicholas, Bau, Claiton HD, Baune, Bernhard T, Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M, Bigdeli, Tim B, Binder, Elisabeth B, Boehnke, Michael, Boks, Marco P, Bosch, Rosa, Braff, David L, Mullins, Niamh, Mullins, Niamh, Kang, JooEun, Campos, Adrian I, Coleman, Jonathan RI, Edwards, Alexis C, Galfalvy, Hanga, Levey, Daniel F, Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J, Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D, Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B, Bergen, Andrew W, Berrettini, Wade H, Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J, Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M, Gallinger, Steven, Glatt, Stephen J, Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A, Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Keel, Pamela K, Kennedy, James L, Klump, Kelly L, Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J, Marshall, Christian R, Mitchell, James E, Monson, Eric T, Myers, Richard M, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W, Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M, Treasure, Janet, Tsuang, Ming T, Witt, Stephanie H, Woodside, D Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M, Alda, Martin, Alfredsson, Lars, Andreassen, Ole A, Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M Helena, Bass, Nicholas, Bau, Claiton HD, Baune, Bernhard T, Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M, Bigdeli, Tim B, Binder, Elisabeth B, Boehnke, Michael, Boks, Marco P, Bosch, Rosa, and Braff, David L
Abstract: BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
Published: 2022

33. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Mullins, Niamh, Kang, JooEun, Campos, Adrian I., Coleman, Jonathan R. I., Edwards, Alexis C., Galfalvy, Hanga, Levey, Daniel F., Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J., Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D., Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B., Bergen, Andrew W., Berrettini, Wade H., Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J., Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M., Gallinger, Steven, Glatt, Stephen J., Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Klump, Kelly L., Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J., Marshall, Christian R., Mitchell, James E., Monson, Eric T., Myers, Richard M., Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M., Treasure, Janet, Tsuang, Ming T., Witt, Stephanie H., Woodside, D. Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M., Alda, Martin, Alfredsson, Lars, Andreassen, Ole A., Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M. Helena, Bass, Nicholas, Bau, Claiton H. D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Bosch, Rosa, Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Casas, Miguel, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Craig, David, Degenhardt, Franziska, Djurovic, Srdjan, Edenberg, Howard J., Fanous, Ayman H., Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Fullerton, Janice M., Gatt, Justine M., Gejman, Pablo V., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamilton, Steven P., Hamshere, Marian L., Hartmann, Annette, Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Konte, Bettina, Krebs, Marie-Odile, Landén, Mikael, Lawrence, Jacob, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Lucae, Susanne, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Medland, Sarah E., Mehta, Divya, Melle, Ingrid, Milaneschi, Yuri, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nievergelt, Caroline, Nimgaonkar, Vishwajit, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W. J. H., Pimm, Jonathan, Pistis, Giorgio, Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Rujescu, Dan, Sánchez-Mora, Cristina, Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Shyn, Stanley I., Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J. S., Spalletta, Gianfranco, Strauss, John S., Świątkowska, Beata, Trzaskowski, Maciej, Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T. R., Shannon Weickert, Cynthia, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Ashley-Koch, Allison E., Beckham, Jean C., Hauser, Elizabeth R., Hauser, Michael A., Kimbrel, Nathan A., Lindquist, Jennifer H., McMahon, Benjamin, Oslin, David W., Qin, Xuejun, Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Erlangsen, Annette, Esko, Tõnu, Gelernter, Joel, Hougaard, David M., Kessler, Ronald C., Kranzler, Henry R., Li, Qingqin S., Martin, Nicholas G., McIntosh, Andrew M., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Ursano, Robert J., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Bulik, Cynthia M., Coon, Hilary, Demontis, Ditte, Docherty, Anna R., Kuo, Po-Hsiu, Lewis, Cathryn M., Mann, J. John, Rentería, Miguel E., Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Streit, Fabian, Willour, Virginia, Ruderfer, Douglas M., Mullins, Niamh, Kang, JooEun, Campos, Adrian I., Coleman, Jonathan R. I., Edwards, Alexis C., Galfalvy, Hanga, Levey, Daniel F., Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J., Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D., Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B., Bergen, Andrew W., Berrettini, Wade H., Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J., Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M., Gallinger, Steven, Glatt, Stephen J., Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Klump, Kelly L., Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J., Marshall, Christian R., Mitchell, James E., Monson, Eric T., Myers, Richard M., Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M., Treasure, Janet, Tsuang, Ming T., Witt, Stephanie H., Woodside, D. Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M., Alda, Martin, Alfredsson, Lars, Andreassen, Ole A., Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M. Helena, Bass, Nicholas, Bau, Claiton H. D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Bosch, Rosa, Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Casas, Miguel, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Craig, David, Degenhardt, Franziska, Djurovic, Srdjan, Edenberg, Howard J., Fanous, Ayman H., Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Fullerton, Janice M., Gatt, Justine M., Gejman, Pablo V., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamilton, Steven P., Hamshere, Marian L., Hartmann, Annette, Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Konte, Bettina, Krebs, Marie-Odile, Landén, Mikael, Lawrence, Jacob, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Lucae, Susanne, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Medland, Sarah E., Mehta, Divya, Melle, Ingrid, Milaneschi, Yuri, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nievergelt, Caroline, Nimgaonkar, Vishwajit, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W. J. H., Pimm, Jonathan, Pistis, Giorgio, Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Rujescu, Dan, Sánchez-Mora, Cristina, Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Shyn, Stanley I., Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J. S., Spalletta, Gianfranco, Strauss, John S., Świątkowska, Beata, Trzaskowski, Maciej, Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T. R., Shannon Weickert, Cynthia, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Ashley-Koch, Allison E., Beckham, Jean C., Hauser, Elizabeth R., Hauser, Michael A., Kimbrel, Nathan A., Lindquist, Jennifer H., McMahon, Benjamin, Oslin, David W., Qin, Xuejun, Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Erlangsen, Annette, Esko, Tõnu, Gelernter, Joel, Hougaard, David M., Kessler, Ronald C., Kranzler, Henry R., Li, Qingqin S., Martin, Nicholas G., McIntosh, Andrew M., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Ursano, Robert J., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Bulik, Cynthia M., Coon, Hilary, Demontis, Ditte, Docherty, Anna R., Kuo, Po-Hsiu, Lewis, Cathryn M., Mann, J. John, Rentería, Miguel E., Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Streit, Fabian, Willour, Virginia, and Ruderfer, Douglas M.
Abstract: BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
Published: 2022
Full Text: View/download PDF

34. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Mullins, Niamh, Kang, JooEun, Campos, Adrian I., Coleman, Jonathan R. I., Edwards, Alexis C., Galfalvy, Hanga, Levey, Daniel F., Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J., Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D., Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B., Bergen, Andrew W., Berrettini, Wade H., Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J., Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M., Gallinger, Steven, Glatt, Stephen J., Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Klump, Kelly L., Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J., Marshall, Christian R., Mitchell, James E., Monson, Eric T., Myers, Richard M., Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M., Treasure, Janet, Tsuang, Ming T., Witt, Stephanie H., Woodside, D. Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M., Alda, Martin, Alfredsson, Lars, Andreassen, Ole A., Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M. Helena, Bass, Nicholas, Bau, Claiton H. D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Bosch, Rosa, Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Casas, Miguel, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Craig, David, Degenhardt, Franziska, Djurovic, Srdjan, Edenberg, Howard J., Fanous, Ayman H., Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Fullerton, Janice M., Gatt, Justine M., Gejman, Pablo V., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamilton, Steven P., Hamshere, Marian L., Hartmann, Annette, Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Konte, Bettina, Krebs, Marie-Odile, Landén, Mikael, Lawrence, Jacob, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Lucae, Susanne, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Medland, Sarah E., Mehta, Divya, Melle, Ingrid, Milaneschi, Yuri, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nievergelt, Caroline, Nimgaonkar, Vishwajit, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W. J. H., Pimm, Jonathan, Pistis, Giorgio, Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Rujescu, Dan, Sánchez-Mora, Cristina, Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Shyn, Stanley I., Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J. S., Spalletta, Gianfranco, Strauss, John S., Świątkowska, Beata, Trzaskowski, Maciej, Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T. R., Shannon Weickert, Cynthia, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Ashley-Koch, Allison E., Beckham, Jean C., Hauser, Elizabeth R., Hauser, Michael A., Kimbrel, Nathan A., Lindquist, Jennifer H., McMahon, Benjamin, Oslin, David W., Qin, Xuejun, Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Erlangsen, Annette, Esko, Tõnu, Gelernter, Joel, Hougaard, David M., Kessler, Ronald C., Kranzler, Henry R., Li, Qingqin S., Martin, Nicholas G., McIntosh, Andrew M., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Ursano, Robert J., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Bulik, Cynthia M., Coon, Hilary, Demontis, Ditte, Docherty, Anna R., Kuo, Po-Hsiu, Lewis, Cathryn M., Mann, J. John, Rentería, Miguel E., Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Streit, Fabian, Willour, Virginia, Ruderfer, Douglas M., Mullins, Niamh, Kang, JooEun, Campos, Adrian I., Coleman, Jonathan R. I., Edwards, Alexis C., Galfalvy, Hanga, Levey, Daniel F., Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J., Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D., Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B., Bergen, Andrew W., Berrettini, Wade H., Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J., Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M., Gallinger, Steven, Glatt, Stephen J., Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Klump, Kelly L., Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J., Marshall, Christian R., Mitchell, James E., Monson, Eric T., Myers, Richard M., Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M., Treasure, Janet, Tsuang, Ming T., Witt, Stephanie H., Woodside, D. Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M., Alda, Martin, Alfredsson, Lars, Andreassen, Ole A., Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M. Helena, Bass, Nicholas, Bau, Claiton H. D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Bosch, Rosa, Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Casas, Miguel, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Craig, David, Degenhardt, Franziska, Djurovic, Srdjan, Edenberg, Howard J., Fanous, Ayman H., Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Fullerton, Janice M., Gatt, Justine M., Gejman, Pablo V., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamilton, Steven P., Hamshere, Marian L., Hartmann, Annette, Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Konte, Bettina, Krebs, Marie-Odile, Landén, Mikael, Lawrence, Jacob, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Lucae, Susanne, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Medland, Sarah E., Mehta, Divya, Melle, Ingrid, Milaneschi, Yuri, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nievergelt, Caroline, Nimgaonkar, Vishwajit, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W. J. H., Pimm, Jonathan, Pistis, Giorgio, Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Rujescu, Dan, Sánchez-Mora, Cristina, Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Shyn, Stanley I., Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J. S., Spalletta, Gianfranco, Strauss, John S., Świątkowska, Beata, Trzaskowski, Maciej, Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T. R., Shannon Weickert, Cynthia, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Ashley-Koch, Allison E., Beckham, Jean C., Hauser, Elizabeth R., Hauser, Michael A., Kimbrel, Nathan A., Lindquist, Jennifer H., McMahon, Benjamin, Oslin, David W., Qin, Xuejun, Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Erlangsen, Annette, Esko, Tõnu, Gelernter, Joel, Hougaard, David M., Kessler, Ronald C., Kranzler, Henry R., Li, Qingqin S., Martin, Nicholas G., McIntosh, Andrew M., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Ursano, Robert J., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Bulik, Cynthia M., Coon, Hilary, Demontis, Ditte, Docherty, Anna R., Kuo, Po-Hsiu, Lewis, Cathryn M., Mann, J. John, Rentería, Miguel E., Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Streit, Fabian, Willour, Virginia, and Ruderfer, Douglas M.
Abstract: BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
Published: 2022
Full Text: View/download PDF

35. ASO Visual Abstract : Systematic Review and Meta-analysis of Prognostic Factors for Early Recurrence in Intrahepatic Cholangiocarcinoma After Curative-Intent Resection

Author: Choi, Woo Jin, Williams, Phil J., Claasen, Marco, Ivanics, Tommy, Englesakis, Marina, Gallinger, Steven, Hansen, Bettina, Sapisochin, Gonzalo, Choi, Woo Jin, Williams, Phil J., Claasen, Marco, Ivanics, Tommy, Englesakis, Marina, Gallinger, Steven, Hansen, Bettina, and Sapisochin, Gonzalo
Published: 2022
Full Text: View/download PDF

36. Systematic Review and Meta-Analysis of Prognostic Factors for Early Recurrence in Intrahepatic Cholangiocarcinoma After Curative-Intent Resection

Author: Choi, Woo Jin, Williams, Phil J., Claasen, Marco P. A. W., Ivanics, Tommy, Englesakis, Marina, Gallinger, Steven, Hansen, Bettina, Sapisochin, Gonzalo, Choi, Woo Jin, Williams, Phil J., Claasen, Marco P. A. W., Ivanics, Tommy, Englesakis, Marina, Gallinger, Steven, Hansen, Bettina, and Sapisochin, Gonzalo
Abstract: Background Recurrence rates of intrahepatic cholangiocarcinoma (iCCA) after curative hepatectomy are as high as 50% to 70%, and about half of these recurrences occur within 2 years. This systematic review aims to define prognostic factors (PFs) for early recurrence (ER, within 24 months) and 24-month disease-free survival (DFS) after curative-intent iCCA resections. Methods Systematic searching was performed from database inception to 14 January 2021. Duplicate independent review and data extraction were performed. Data on 13 predefined PFs were collected. Meta-analysis was performed on PFs for ER and summarized using forest plots. The Quality in Prognostic Factor Studies tool was used for risk-of-bias assessment. Results The study enrolled 10 studies comprising 4158 patients during an accrual period ranging from 1990 to 2016. In the risk-of-bias assessment of patients who experienced ER after curative-intent iCCA resection, six studies were rated as low risk and four as moderate risk (49.6%; 95% confidence interval [CI], 49.2-50.0). Nine studies were pooled for meta-analysis. Of the postoperative PFs, multiple tumors, microvascular invasion, macrovascular invasion, lymph node metastasis, and R1 resection were associated with an increased hazard for ER or a reduced 24-month DFS, and the opposite was observed for receipt of adjuvant chemo/radiation therapy. Of the preoperative factors, cirrhosis, sex, HBV status were not associated with ER or 24-month DFS. Conclusion The findings from this systematic review could allow for improved surveillance, prognostication, and treatment decision-making for patients with resectable iCCAs. Further well-designed prospective studies are needed to explore prognostic factors for iCCA ER with a focus on preoperative variables.
Published: 2022
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37. Diabetes mellitus in relation to colorectal tumor molecular subtypes : a pooled analysis of more than 9000 cases

Author: Harlid, Sophia, van Guelpen, Bethany, Qu, Conghui, Gylling, Björn, Aglago, Elom K., Amitay, Efrat L., Brenner, Hermann, Buchanan, Daniel D., Campbell, Peter T., Cao, Yin, Chan, Andrew T., Chang-Claude, Jenny, Drew, David A., Figueiredo, Jane C., French, Amy J., Gallinger, Steven, Giannakis, Marios, Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Newton, Christina C., Nowak, Jonathan A., Obón-Santacana, Mireia, Ogino, Shuji, Potter, John D., Song, Mingyang, Steinfelder, Robert S., Sun, Wei, Thibodeau, Stephen N., Toland, Amanda E., Ugai, Tomotaka, Um, Caroline Y., Woods, Michael O., Phipps, Amanda I., Harrison, Tabitha, Peters, Ulrike, Harlid, Sophia, van Guelpen, Bethany, Qu, Conghui, Gylling, Björn, Aglago, Elom K., Amitay, Efrat L., Brenner, Hermann, Buchanan, Daniel D., Campbell, Peter T., Cao, Yin, Chan, Andrew T., Chang-Claude, Jenny, Drew, David A., Figueiredo, Jane C., French, Amy J., Gallinger, Steven, Giannakis, Marios, Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Newton, Christina C., Nowak, Jonathan A., Obón-Santacana, Mireia, Ogino, Shuji, Potter, John D., Song, Mingyang, Steinfelder, Robert S., Sun, Wei, Thibodeau, Stephen N., Toland, Amanda E., Ugai, Tomotaka, Um, Caroline Y., Woods, Michael O., Phipps, Amanda I., Harrison, Tabitha, and Peters, Ulrike
Abstract: Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj: 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj: 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.
Published: 2022
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38. Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival

Author: Labadie, Julia D., Savas, Sevtap, Harrison, Tabitha A., Banbury, Barb, Huang, Yuhan, Buchanan, Daniel D., Campbell, Peter T., Gallinger, Steven J., Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Ogino, Shuji, Phipps, Amanda I., Slattery, Martha L., Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Hua, Xinwei, Figuieredo, Jane C., Pai, Rish K., Nassir, Rami, Qi, Lihong, Chan, Andrew T., Peters, Ulrike, Newcomb, Polly A., Labadie, Julia D., Savas, Sevtap, Harrison, Tabitha A., Banbury, Barb, Huang, Yuhan, Buchanan, Daniel D., Campbell, Peter T., Gallinger, Steven J., Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Ogino, Shuji, Phipps, Amanda I., Slattery, Martha L., Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Hua, Xinwei, Figuieredo, Jane C., Pai, Rish K., Nassir, Rami, Qi, Lihong, Chan, Andrew T., Peters, Ulrike, and Newcomb, Polly A.
Abstract: Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10–8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30–1.69, p = 8.47 × 10–9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65–2.77, p = 9.19 × 10–9 and rs144717887, HR = 2.01, 95% CI 1.57–2.58, p = 3.14 × 10–8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.
Published: 2022
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39. Molecular and Pathology Features of Colorectal Tumors and Patient Outcomes Are Associated with Fusobacterium nucleatum and Its Subspecies animalis

Author: Borozan, Ivan, Zaidi, Syed H., Harrison, Tabitha A., Phipps, Amanda I., Zheng, Jiayin, Lee, Stephen, Trinh, Quang M., Steinfelder, Robert S., Adams, Jeremy, Banbury, Barbara L., Berndt, Sonja I., Brezina, Stefanie, Buchanan, Daniel D., Bullman, Susan, Cao, Yin, Farris III, Alton B., Figueiredo, Jane C., Giannakis, Marios, Heisler, Lawrence E., Hopper, John L., Lin, Yi, Luo, Xuemei, Nishihara, Reiko, Mardis, Elaine R., Papadopoulos, Nickolas, Qu, Conghui, Reid, Emma E.G., Thibodeau, Stephen N., Harlid, Sophia, Um, Caroline Y., Hsu, Li, Gsur, Andrea, Campbell, Peter T., Gallinger, Steven, Newcomb, Polly A., Ogino, Shuji, Sun, Wei, Hudson, Thomas J., Ferretti, Vincent, Peters, Ulrike, Borozan, Ivan, Zaidi, Syed H., Harrison, Tabitha A., Phipps, Amanda I., Zheng, Jiayin, Lee, Stephen, Trinh, Quang M., Steinfelder, Robert S., Adams, Jeremy, Banbury, Barbara L., Berndt, Sonja I., Brezina, Stefanie, Buchanan, Daniel D., Bullman, Susan, Cao, Yin, Farris III, Alton B., Figueiredo, Jane C., Giannakis, Marios, Heisler, Lawrence E., Hopper, John L., Lin, Yi, Luo, Xuemei, Nishihara, Reiko, Mardis, Elaine R., Papadopoulos, Nickolas, Qu, Conghui, Reid, Emma E.G., Thibodeau, Stephen N., Harlid, Sophia, Um, Caroline Y., Hsu, Li, Gsur, Andrea, Campbell, Peter T., Gallinger, Steven, Newcomb, Polly A., Ogino, Shuji, Sun, Wei, Hudson, Thomas J., Ferretti, Vincent, and Peters, Ulrike
Abstract: Background: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. Methods: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer-specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations. Results: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer-specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07-3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. Conclusions: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes.
Published: 2022
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40. Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival

Author: Labadie, Julia D., Savas, Sevtap, Harrison, Tabitha A., Banbury, Barb, Huang, Yuhan, Buchanan, Daniel D., Campbell, Peter T., Gallinger, Steven J., Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Ogino, Shuji, Phipps, Amanda I., Slattery, Martha L., Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Hua, Xinwei, Figuieredo, Jane C., Pai, Rish K., Nassir, Rami, Qi, Lihong, Chan, Andrew T., Peters, Ulrike, Newcomb, Polly A., Labadie, Julia D., Savas, Sevtap, Harrison, Tabitha A., Banbury, Barb, Huang, Yuhan, Buchanan, Daniel D., Campbell, Peter T., Gallinger, Steven J., Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Ogino, Shuji, Phipps, Amanda I., Slattery, Martha L., Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Hua, Xinwei, Figuieredo, Jane C., Pai, Rish K., Nassir, Rami, Qi, Lihong, Chan, Andrew T., Peters, Ulrike, and Newcomb, Polly A.
Abstract: Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10–8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30–1.69, p = 8.47 × 10–9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65–2.77, p = 9.19 × 10–9 and rs144717887, HR = 2.01, 95% CI 1.57–2.58, p = 3.14 × 10–8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.
Published: 2022
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41. Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival

Author: Labadie, Julia D., Savas, Sevtap, Harrison, Tabitha A., Banbury, Barb, Huang, Yuhan, Buchanan, Daniel D., Campbell, Peter T., Gallinger, Steven J., Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Ogino, Shuji, Phipps, Amanda I., Slattery, Martha L., Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Hua, Xinwei, Figuieredo, Jane C., Pai, Rish K., Nassir, Rami, Qi, Lihong, Chan, Andrew T., Peters, Ulrike, Newcomb, Polly A., Labadie, Julia D., Savas, Sevtap, Harrison, Tabitha A., Banbury, Barb, Huang, Yuhan, Buchanan, Daniel D., Campbell, Peter T., Gallinger, Steven J., Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Ogino, Shuji, Phipps, Amanda I., Slattery, Martha L., Steinfelder, Robert S., Sun, Wei, van Guelpen, Bethany, Hua, Xinwei, Figuieredo, Jane C., Pai, Rish K., Nassir, Rami, Qi, Lihong, Chan, Andrew T., Peters, Ulrike, and Newcomb, Polly A.
Abstract: Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10–8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30–1.69, p = 8.47 × 10–9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65–2.77, p = 9.19 × 10–9 and rs144717887, HR = 2.01, 95% CI 1.57–2.58, p = 3.14 × 10–8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.
Published: 2022
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42. Common Genetic Variation and Age of Onset of Anorexia Nervosa

Author: Watson, Hunna J., Thornton, Laura M., Yilmaz, Zeynep, Baker, Jessica H., Coleman, Jonathan R.I., Adan, Roger A.H., Alfredsson, Lars, Andreassen, Ole A., Ask, Helga, Berrettini, Wade H., Boehnke, Michael, Boehm, Ilka, Boni, Claudette, Buehren, Katharina, Bulant, Josef, Burghardt, Roland, Chang, Xiao, Cichon, Sven, Cone, Roger D., Courtet, Philippe, Crow, Scott, Crowley, James J., Danner, Unna N., de Zwaan, Martina, Dedoussis, George, DeSocio, Janiece E., Dick, Danielle M., Dikeos, Dimitris, Dina, Christian, Djurovic, Srdjan, Dmitrzak-Weglarz, Monika, Docampo-Martinez, Elisa, Duriez, Philibert, Egberts, Karin, Ehrlich, Stefan, Eriksson, Johan G., Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Fernández-Aranda, Fernando, Fichter, Manfred M., Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J., Frei, Oleksandr, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacòs, Mònica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hauser, Joanna, Havdahl, Alexandra, Hebebrand, Johannes, Helder, Sietske G., Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Hübel, Christopher, Hudson, James I., Imgart, Hartmut, Jamain, Stephanie, Janout, Vladimir, Jiménez-Murcia, Susana, Jones, Ian R., Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaprio, Jaakko, Karhunen, Leila, Kas, Martien J.H., Keel, Pamela K., Kennedy, James L., Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Klareskog, Lars, Klump, Kelly L., Knudsen, Gun Peggy S., La Via, Maria C., Le Hellard, Stephanie, Leboyer, Marion, Li, Dong, Lilenfeld, Lisa, Lin, Bochao, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre, Maj, Mario, Marsal, Sara, Marshall, Christian R., Mattingsdal, Morten, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen S., Monteleone, Alessio Maria, Monteleone, Palmiero, Myers, Richard, Navratilova, Marie, Ntalla, Ionna, O'Toole, Julie K., Ophoff, Roel A., Padyukov, Leonid, Pantel, Jacques, Papežová, Hana, Pinto, Dalila, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ripke, Stephan, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Scherag, André, Scherer, Stephen W., Schmidt, Ulrike, Scott, Laura J., Seitz, Jochen, Silén, Yasmina, Šlachtová, Lenka, Slagboom, P. Eline, Slof-Op ‘t Landt, Margarita C.T., Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A., van Furth, Eric F., Walton, Esther, Widen, Elisabeth, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W., Boden, Joseph M., Brandt, Harry, Crawford, Steven, Halmi, Katherine A., Horwood, L. John, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Mitchell, James E., Olsen, Catherine M., Pearson, John F., Pedersen, Nancy L., Strober, Michael, Werge, Thomas, Whiteman, David C., Woodside, D. Blake, Gordon, Scott, Maguire, Sarah, Larsen, Janne T., Parker, Richard, Petersen, Liselotte V., Jordan, Jennifer, Kennedy, Martin, Wade, Tracey D., Birgegård, Andreas, Lichtenstein, Paul, Landén, Mikael, Martin, Nicholas G., Mortensen, Preben Bo, Breen, Gerome, Bulik, Cynthia M., Watson, Hunna J., Thornton, Laura M., Yilmaz, Zeynep, Baker, Jessica H., Coleman, Jonathan R.I., Adan, Roger A.H., Alfredsson, Lars, Andreassen, Ole A., Ask, Helga, Berrettini, Wade H., Boehnke, Michael, Boehm, Ilka, Boni, Claudette, Buehren, Katharina, Bulant, Josef, Burghardt, Roland, Chang, Xiao, Cichon, Sven, Cone, Roger D., Courtet, Philippe, Crow, Scott, Crowley, James J., Danner, Unna N., de Zwaan, Martina, Dedoussis, George, DeSocio, Janiece E., Dick, Danielle M., Dikeos, Dimitris, Dina, Christian, Djurovic, Srdjan, Dmitrzak-Weglarz, Monika, Docampo-Martinez, Elisa, Duriez, Philibert, Egberts, Karin, Ehrlich, Stefan, Eriksson, Johan G., Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Fernández-Aranda, Fernando, Fichter, Manfred M., Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J., Frei, Oleksandr, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacòs, Mònica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hauser, Joanna, Havdahl, Alexandra, Hebebrand, Johannes, Helder, Sietske G., Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Hübel, Christopher, Hudson, James I., Imgart, Hartmut, Jamain, Stephanie, Janout, Vladimir, Jiménez-Murcia, Susana, Jones, Ian R., Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaprio, Jaakko, Karhunen, Leila, Kas, Martien J.H., Keel, Pamela K., Kennedy, James L., Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Klareskog, Lars, Klump, Kelly L., Knudsen, Gun Peggy S., La Via, Maria C., Le Hellard, Stephanie, Leboyer, Marion, Li, Dong, Lilenfeld, Lisa, Lin, Bochao, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre, Maj, Mario, Marsal, Sara, Marshall, Christian R., Mattingsdal, Morten, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen S., Monteleone, Alessio Maria, Monteleone, Palmiero, Myers, Richard, Navratilova, Marie, Ntalla, Ionna, O'Toole, Julie K., Ophoff, Roel A., Padyukov, Leonid, Pantel, Jacques, Papežová, Hana, Pinto, Dalila, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ripke, Stephan, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Scherag, André, Scherer, Stephen W., Schmidt, Ulrike, Scott, Laura J., Seitz, Jochen, Silén, Yasmina, Šlachtová, Lenka, Slagboom, P. Eline, Slof-Op ‘t Landt, Margarita C.T., Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A., van Furth, Eric F., Walton, Esther, Widen, Elisabeth, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W., Boden, Joseph M., Brandt, Harry, Crawford, Steven, Halmi, Katherine A., Horwood, L. John, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Mitchell, James E., Olsen, Catherine M., Pearson, John F., Pedersen, Nancy L., Strober, Michael, Werge, Thomas, Whiteman, David C., Woodside, D. Blake, Gordon, Scott, Maguire, Sarah, Larsen, Janne T., Parker, Richard, Petersen, Liselotte V., Jordan, Jennifer, Kennedy, Martin, Wade, Tracey D., Birgegård, Andreas, Lichtenstein, Paul, Landén, Mikael, Martin, Nicholas G., Mortensen, Preben Bo, Breen, Gerome, and Bulik, Cynthia M.
Abstract: Background Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism–h2) were 0.01–0.04 for age of onset, 0.16–0.25 for early-onset AN, and 0.17–0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction., Background: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche. Methods: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism–h2) were 0.01–0.04 for age of onset, 0.16–0.25 for early-onset AN, and 0.17–0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
Published: 2022

43. 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
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44. Is it safe to administer neoadjuvant chemotherapy to patients undergoing hepatectomy for intrahepatic cholangiocarcinoma? : ACS-NSQIP propensity-matched analysis

Author: Choi, Woo Jin, Ivanics, Tommy, Claasen, Marco P. A. W., Gallinger, Steven, Hansen, Bettina, Sapisochin, Gonzalo, Choi, Woo Jin, Ivanics, Tommy, Claasen, Marco P. A. W., Gallinger, Steven, Hansen, Bettina, and Sapisochin, Gonzalo
Abstract: Background: The use of neoadjuvant chemotherapy (NAC) in patients with intrahepatic chol-angiocarcinoma (iCCA) is increasing. The objective of this study was to compare the 30-day post-operative complications and length-of-stay (LOS) between patients undergoing hepatectomy for iCCA with and without NAC. Methods: A retrospective study was conducted using the ACS-NSQIP database queried from 2014 to 2018. Patients with NAC receipt were propensity-score matched into 1:3 ratio with controls using the greedy-matching algorithm and a caliper of 0.2. Logistic and Poisson regression models were used to estimate the effect sizes. Results: A total of 1508 patients who underwent hepatectomy for iCCA were included. 706 patients remained after matching and balance were achieved. The NAC group had 110 (60.1%) complications vs. 289 (55.3%) complications in the non-NAC group (p = 0.29). NAC was not associated with worse 30-day postoperative complications [OR 1.24, 95% CI: 0.87-1.76; p = 0.24]. Post-operative LOS in the NAC group was 8.56 days (mean, SD 7.4) vs. non-NAC group 9.27 days (mean, SD 8.41, p = 0.32). NAC was not associated with longer post-operative LOS [RR 0.93, 95% CI:0.80, 1.08; p = 0.32]. Conclusion: NAC may be safely administered without increasing the risk of 30-day complications or post-operative hospital LOS.
Published: 2022
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45. Diabetes mellitus in relation to colorectal tumor molecular subtypes : a pooled analysis of more than 9000 cases

Author: Harlid, Sophia, van Guelpen, Bethany, Qu, Conghui, Gylling, Björn, Aglago, Elom K., Amitay, Efrat L., Brenner, Hermann, Buchanan, Daniel D., Campbell, Peter T., Cao, Yin, Chan, Andrew T., Chang-Claude, Jenny, Drew, David A., Figueiredo, Jane C., French, Amy J., Gallinger, Steven, Giannakis, Marios, Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Newton, Christina C., Nowak, Jonathan A., Obón-Santacana, Mireia, Ogino, Shuji, Potter, John D., Song, Mingyang, Steinfelder, Robert S., Sun, Wei, Thibodeau, Stephen N., Toland, Amanda E., Ugai, Tomotaka, Um, Caroline Y., Woods, Michael O., Phipps, Amanda I., Harrison, Tabitha, Peters, Ulrike, Harlid, Sophia, van Guelpen, Bethany, Qu, Conghui, Gylling, Björn, Aglago, Elom K., Amitay, Efrat L., Brenner, Hermann, Buchanan, Daniel D., Campbell, Peter T., Cao, Yin, Chan, Andrew T., Chang-Claude, Jenny, Drew, David A., Figueiredo, Jane C., French, Amy J., Gallinger, Steven, Giannakis, Marios, Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Newton, Christina C., Nowak, Jonathan A., Obón-Santacana, Mireia, Ogino, Shuji, Potter, John D., Song, Mingyang, Steinfelder, Robert S., Sun, Wei, Thibodeau, Stephen N., Toland, Amanda E., Ugai, Tomotaka, Um, Caroline Y., Woods, Michael O., Phipps, Amanda I., Harrison, Tabitha, and Peters, Ulrike
Abstract: Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj: 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj: 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.
Published: 2022
Full Text: View/download PDF

46. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

Author: Mullins, Niamh, Mullins, Niamh, Kang, JooEun, Campos, Adrian I, Coleman, Jonathan RI, Edwards, Alexis C, Galfalvy, Hanga, Levey, Daniel F, Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J, Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D, Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B, Bergen, Andrew W, Berrettini, Wade H, Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J, Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M, Gallinger, Steven, Glatt, Stephen J, Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A, Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Keel, Pamela K, Kennedy, James L, Klump, Kelly L, Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J, Marshall, Christian R, Mitchell, James E, Monson, Eric T, Myers, Richard M, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W, Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M, Treasure, Janet, Tsuang, Ming T, Witt, Stephanie H, Woodside, D Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M, Alda, Martin, Alfredsson, Lars, Andreassen, Ole A, Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M Helena, Bass, Nicholas, Bau, Claiton HD, Baune, Bernhard T, Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M, Bigdeli, Tim B, Binder, Elisabeth B, Boehnke, Michael, Boks, Marco P, Bosch, Rosa, Braff, David L, Mullins, Niamh, Mullins, Niamh, Kang, JooEun, Campos, Adrian I, Coleman, Jonathan RI, Edwards, Alexis C, Galfalvy, Hanga, Levey, Daniel F, Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J, Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D, Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B, Bergen, Andrew W, Berrettini, Wade H, Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J, Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M, Gallinger, Steven, Glatt, Stephen J, Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A, Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Keel, Pamela K, Kennedy, James L, Klump, Kelly L, Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J, Marshall, Christian R, Mitchell, James E, Monson, Eric T, Myers, Richard M, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W, Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M, Treasure, Janet, Tsuang, Ming T, Witt, Stephanie H, Woodside, D Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M, Alda, Martin, Alfredsson, Lars, Andreassen, Ole A, Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M Helena, Bass, Nicholas, Bau, Claiton HD, Baune, Bernhard T, Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M, Bigdeli, Tim B, Binder, Elisabeth B, Boehnke, Michael, Boks, Marco P, Bosch, Rosa, and Braff, David L
Abstract: BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
Published: 2022

47. Diabetes mellitus in relation to colorectal tumor molecular subtypes : a pooled analysis of more than 9000 cases

Author: Harlid, Sophia, van Guelpen, Bethany, Qu, Conghui, Gylling, Björn, Aglago, Elom K., Amitay, Efrat L., Brenner, Hermann, Buchanan, Daniel D., Campbell, Peter T., Cao, Yin, Chan, Andrew T., Chang-Claude, Jenny, Drew, David A., Figueiredo, Jane C., French, Amy J., Gallinger, Steven, Giannakis, Marios, Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Newton, Christina C., Nowak, Jonathan A., Obón-Santacana, Mireia, Ogino, Shuji, Potter, John D., Song, Mingyang, Steinfelder, Robert S., Sun, Wei, Thibodeau, Stephen N., Toland, Amanda E., Ugai, Tomotaka, Um, Caroline Y., Woods, Michael O., Phipps, Amanda I., Harrison, Tabitha, Peters, Ulrike, Harlid, Sophia, van Guelpen, Bethany, Qu, Conghui, Gylling, Björn, Aglago, Elom K., Amitay, Efrat L., Brenner, Hermann, Buchanan, Daniel D., Campbell, Peter T., Cao, Yin, Chan, Andrew T., Chang-Claude, Jenny, Drew, David A., Figueiredo, Jane C., French, Amy J., Gallinger, Steven, Giannakis, Marios, Giles, Graham G., Gunter, Marc J., Hoffmeister, Michael, Hsu, Li, Jenkins, Mark A., Lin, Yi, Moreno, Victor, Murphy, Neil, Newcomb, Polly A., Newton, Christina C., Nowak, Jonathan A., Obón-Santacana, Mireia, Ogino, Shuji, Potter, John D., Song, Mingyang, Steinfelder, Robert S., Sun, Wei, Thibodeau, Stephen N., Toland, Amanda E., Ugai, Tomotaka, Um, Caroline Y., Woods, Michael O., Phipps, Amanda I., Harrison, Tabitha, and Peters, Ulrike
Abstract: Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj: 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj: 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.
Published: 2022
Full Text: View/download PDF

48. 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

49. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Mullins, Niamh, Kang, JooEun, Campos, Adrian I., Coleman, Jonathan R. I., Edwards, Alexis C., Galfalvy, Hanga, Levey, Daniel F., Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J., Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D., Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B., Bergen, Andrew W., Berrettini, Wade H., Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J., Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M., Gallinger, Steven, Glatt, Stephen J., Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Klump, Kelly L., Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J., Marshall, Christian R., Mitchell, James E., Monson, Eric T., Myers, Richard M., Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M., Treasure, Janet, Tsuang, Ming T., Witt, Stephanie H., Woodside, D. Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M., Alda, Martin, Alfredsson, Lars, Andreassen, Ole A., Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M. Helena, Bass, Nicholas, Bau, Claiton H. D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Bosch, Rosa, Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Casas, Miguel, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Craig, David, Degenhardt, Franziska, Djurovic, Srdjan, Edenberg, Howard J., Fanous, Ayman H., Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Fullerton, Janice M., Gatt, Justine M., Gejman, Pablo V., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamilton, Steven P., Hamshere, Marian L., Hartmann, Annette, Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Konte, Bettina, Krebs, Marie-Odile, Landén, Mikael, Lawrence, Jacob, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Lucae, Susanne, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Medland, Sarah E., Mehta, Divya, Melle, Ingrid, Milaneschi, Yuri, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nievergelt, Caroline, Nimgaonkar, Vishwajit, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W. J. H., Pimm, Jonathan, Pistis, Giorgio, Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Rujescu, Dan, Sánchez-Mora, Cristina, Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Shyn, Stanley I., Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J. S., Spalletta, Gianfranco, Strauss, John S., Świątkowska, Beata, Trzaskowski, Maciej, Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T. R., Shannon Weickert, Cynthia, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Ashley-Koch, Allison E., Beckham, Jean C., Hauser, Elizabeth R., Hauser, Michael A., Kimbrel, Nathan A., Lindquist, Jennifer H., McMahon, Benjamin, Oslin, David W., Qin, Xuejun, Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Erlangsen, Annette, Esko, Tõnu, Gelernter, Joel, Hougaard, David M., Kessler, Ronald C., Kranzler, Henry R., Li, Qingqin S., Martin, Nicholas G., McIntosh, Andrew M., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Ursano, Robert J., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Bulik, Cynthia M., Coon, Hilary, Demontis, Ditte, Docherty, Anna R., Kuo, Po-Hsiu, Lewis, Cathryn M., Mann, J. John, Rentería, Miguel E., Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Streit, Fabian, Willour, Virginia, Ruderfer, Douglas M., Mullins, Niamh, Kang, JooEun, Campos, Adrian I., Coleman, Jonathan R. I., Edwards, Alexis C., Galfalvy, Hanga, Levey, Daniel F., Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J., Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D., Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B., Bergen, Andrew W., Berrettini, Wade H., Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J., Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M., Gallinger, Steven, Glatt, Stephen J., Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Klump, Kelly L., Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J., Marshall, Christian R., Mitchell, James E., Monson, Eric T., Myers, Richard M., Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M., Treasure, Janet, Tsuang, Ming T., Witt, Stephanie H., Woodside, D. Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M., Alda, Martin, Alfredsson, Lars, Andreassen, Ole A., Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M. Helena, Bass, Nicholas, Bau, Claiton H. D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Bosch, Rosa, Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Casas, Miguel, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Craig, David, Degenhardt, Franziska, Djurovic, Srdjan, Edenberg, Howard J., Fanous, Ayman H., Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Fullerton, Janice M., Gatt, Justine M., Gejman, Pablo V., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamilton, Steven P., Hamshere, Marian L., Hartmann, Annette, Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Konte, Bettina, Krebs, Marie-Odile, Landén, Mikael, Lawrence, Jacob, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Lucae, Susanne, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Medland, Sarah E., Mehta, Divya, Melle, Ingrid, Milaneschi, Yuri, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nievergelt, Caroline, Nimgaonkar, Vishwajit, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W. J. H., Pimm, Jonathan, Pistis, Giorgio, Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Rujescu, Dan, Sánchez-Mora, Cristina, Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Shyn, Stanley I., Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J. S., Spalletta, Gianfranco, Strauss, John S., Świątkowska, Beata, Trzaskowski, Maciej, Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T. R., Shannon Weickert, Cynthia, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Ashley-Koch, Allison E., Beckham, Jean C., Hauser, Elizabeth R., Hauser, Michael A., Kimbrel, Nathan A., Lindquist, Jennifer H., McMahon, Benjamin, Oslin, David W., Qin, Xuejun, Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Erlangsen, Annette, Esko, Tõnu, Gelernter, Joel, Hougaard, David M., Kessler, Ronald C., Kranzler, Henry R., Li, Qingqin S., Martin, Nicholas G., McIntosh, Andrew M., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Ursano, Robert J., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Bulik, Cynthia M., Coon, Hilary, Demontis, Ditte, Docherty, Anna R., Kuo, Po-Hsiu, Lewis, Cathryn M., Mann, J. John, Rentería, Miguel E., Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Streit, Fabian, Willour, Virginia, and Ruderfer, Douglas M.
Abstract: BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
Published: 2022
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50. Common Genetic Variation and Age of Onset of Anorexia Nervosa.

Author: Watson, Hunna J, Watson, Hunna J, Thornton, Laura M, Yilmaz, Zeynep, Baker, Jessica H, Coleman, Jonathan RI, Adan, Roger AH, Alfredsson, Lars, Andreassen, Ole A, Ask, Helga, Berrettini, Wade H, Boehnke, Michael, Boehm, Ilka, Boni, Claudette, Buehren, Katharina, Bulant, Josef, Burghardt, Roland, Chang, Xiao, Cichon, Sven, Cone, Roger D, Courtet, Philippe, Crow, Scott, Crowley, James J, Danner, Unna N, de Zwaan, Martina, Dedoussis, George, DeSocio, Janiece E, Dick, Danielle M, Dikeos, Dimitris, Dina, Christian, Djurovic, Srdjan, Dmitrzak-Weglarz, Monika, Docampo-Martinez, Elisa, Duriez, Philibert, Egberts, Karin, Ehrlich, Stefan, Eriksson, Johan G, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Fernández-Aranda, Fernando, Fichter, Manfred M, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J, Frei, Oleksandr, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacòs, Mònica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hauser, Joanna, Havdahl, Alexandra, Hebebrand, Johannes, Helder, Sietske G, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Hübel, Christopher, Hudson, James I, Imgart, Hartmut, Jamain, Stephanie, Janout, Vladimir, Jiménez-Murcia, Susana, Jones, Ian R, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaprio, Jaakko, Karhunen, Leila, Kas, Martien JH, Keel, Pamela K, Kennedy, James L, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Klareskog, Lars, Klump, Kelly L, Knudsen, Gun Peggy S, La Via, Maria C, Le Hellard, Stephanie, Leboyer, Marion, Li, Dong, Lilenfeld, Lisa, Lin, Bochao, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre, Maj, Mario, Marsal, Sara, Marshall, Christian R, Mattingsdal, Morten, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen S, Monteleone, Alessio Maria, Watson, Hunna J, Watson, Hunna J, Thornton, Laura M, Yilmaz, Zeynep, Baker, Jessica H, Coleman, Jonathan RI, Adan, Roger AH, Alfredsson, Lars, Andreassen, Ole A, Ask, Helga, Berrettini, Wade H, Boehnke, Michael, Boehm, Ilka, Boni, Claudette, Buehren, Katharina, Bulant, Josef, Burghardt, Roland, Chang, Xiao, Cichon, Sven, Cone, Roger D, Courtet, Philippe, Crow, Scott, Crowley, James J, Danner, Unna N, de Zwaan, Martina, Dedoussis, George, DeSocio, Janiece E, Dick, Danielle M, Dikeos, Dimitris, Dina, Christian, Djurovic, Srdjan, Dmitrzak-Weglarz, Monika, Docampo-Martinez, Elisa, Duriez, Philibert, Egberts, Karin, Ehrlich, Stefan, Eriksson, Johan G, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Fernández-Aranda, Fernando, Fichter, Manfred M, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J, Frei, Oleksandr, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacòs, Mònica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hauser, Joanna, Havdahl, Alexandra, Hebebrand, Johannes, Helder, Sietske G, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Hübel, Christopher, Hudson, James I, Imgart, Hartmut, Jamain, Stephanie, Janout, Vladimir, Jiménez-Murcia, Susana, Jones, Ian R, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaprio, Jaakko, Karhunen, Leila, Kas, Martien JH, Keel, Pamela K, Kennedy, James L, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Klareskog, Lars, Klump, Kelly L, Knudsen, Gun Peggy S, La Via, Maria C, Le Hellard, Stephanie, Leboyer, Marion, Li, Dong, Lilenfeld, Lisa, Lin, Bochao, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre, Maj, Mario, Marsal, Sara, Marshall, Christian R, Mattingsdal, Morten, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen S, and Monteleone, Alessio Maria
Abstract: BackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.MethodsA secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.ResultsTwo loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h 2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN.ConclusionsOur results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
Published: 2022

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