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1. Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk

Author

Cameron B. Haas, Yu-Ru Su, Paneen Petersen, Xiaoliang Wang, Stephanie A. Bien, Yi Lin, Demetrius Albanes, Stephanie J. Weinstein, Mark A. Jenkins, Jane C. Figueiredo, Polly A. Newcomb, Graham Casey, Loic Le Marchand, Peter T. Campbell, Victor Moreno, John D. Potter, Lori C. Sakoda, Martha L. Slattery, Andrew T. Chan, Li Li, Graham G. Giles, Roger L. Milne, Stephen B. Gruber, Gad Rennert, Michael O. Woods, Steven J. Gallinger, Sonja Berndt, Richard B. Hayes, Wen-Yi Huang, Alicja Wolk, Emily White, Hongmei Nan, Rami Nassir, Noralane M. Lindor, Juan P. Lewinger, Andre E. Kim, David Conti, W. James Gauderman, Daniel D. Buchanan, Ulrike Peters, and Li Hsu

Subjects
Medicine, Science
Abstract

Abstract Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene–environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case–control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E−4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E−4), and Aspartylglucosaminidase (AGA: p = 4.5E−4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.

Published
2022
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2. Validation and functional characterization of GWAS-identified variants for chronic lymphocytic leukemia: a CRuCIAL study

Author

Paloma García-Martín, Ana Moñiz Díez, José Manuel Sánchez Maldonado, Antonio José Cabrera Serrano, Rob ter Horst, Yolanda Benavente, Stefano Landi, Angelica Macauda, Alyssa Clay-Gilmour, Francisca Hernández-Mohedo, Yasmeen Niazi, Pedro González-Sierra, Blanca Espinet, Juan José Rodríguez-Sevilla, Rossana Maffei, Gonzalo Blanco, Matteo Giaccherini, Anna Puiggros, James Cerhan, Roberto Marasca, Marisa Cañadas-Garre, Miguel Ángel López-Nevot, Tzu Chen-Liang, Hauke Thomsen, Irene Gámez, Víctor Moreno, Rafael Marcos-Gragera, María García-Álvarez, Javier Llorca, Andrés Jerez, Sonja Berndt, Aleksandra Butrym, Aaron D. Norman, Delphine Casabonne, Mario Luppi, Susan L. Slager, Kari Hemminki, Yang Li, Miguel Alcoceba, Daniele Campa, Federico Canzian, Silvia de Sanjosé, Asta Försti, Mihai G. Netea, Manuel Jurado, and Juan Sainz

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2022
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3. Polymorphisms of an innate immune gene, toll-like receptor 4, and aggressive prostate cancer risk: a systematic review and meta-analysis.

Author

Pei-Hsuan Weng, Yi-Ling Huang, John H Page, Jen-Hau Chen, Jianfeng Xu, Stella Koutros, Sonja Berndt, Stephen Chanock, Meredith Yeager, John S Witte, Rosalind A Eeles, Douglas F Easton, David E Neal, Jenny Donovan, Freddie C Hamdy, Kenneth R Muir, Graham Giles, Gianluca Severi, Jeffrey R Smith, Carmela R Balistreri, Irene M Shui, and Yen-Ching Chen

Subjects
Medicine, Science
Abstract

Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews.We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls.Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity.TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa.

Published
2014
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4. Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.

Author

Qing Lan, Richard Cawthon, Yutang Gao, Wei Hu, H Dean Hosgood, Francesco Barone-Adesi, Bu-Tian Ji, Bryan Bassig, Wong-Ho Chow, Xiaoou Shu, Qiuyin Cai, Yongbin Xiang, Sonja Berndt, Christopher Kim, Stephen Chanock, Wei Zheng, and Nathaniel Rothman

Subjects
Medicine, Science
Abstract

A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations.

Published
2013
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5. Genome-wide search for gene-gene interactions in colorectal cancer.

Author

Shuo Jiao, Li Hsu, Sonja Berndt, Stéphane Bézieau, Hermann Brenner, Daniel Buchanan, Bette J Caan, Peter T Campbell, Christopher S Carlson, Graham Casey, Andrew T Chan, Jenny Chang-Claude, Stephen Chanock, David V Conti, Keith R Curtis, David Duggan, Steven Gallinger, Stephen B Gruber, Tabitha A Harrison, Richard B Hayes, Brian E Henderson, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Carolyn M Hutter, Rebecca D Jackson, Mark A Jenkins, Elizabeth D Kantor, Laurence N Kolonel, Sébastien Küry, Loic Le Marchand, Mathieu Lemire, Polly A Newcomb, John D Potter, Conghui Qu, Stephanie A Rosse, Robert E Schoen, Fred R Schumacher, Daniela Seminara, Martha L Slattery, Cornelia M Ulrich, Brent W Zanke, and Ulrike Peters

Subjects
Medicine, Science
Abstract

Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p

Published
2012
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6. Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases

Author

Tomotaka Ugai, Koichiro Haruki, Tabitha A. Harrison, Yin Cao, Conghui Qu, Andrew T. Chan, Peter T. Campbell, Naohiko Akimoto, Sonja Berndt, Hermann Brenner, Daniel D. Buchanan, Jenny Chang-Claude, Kenji Fujiyoshi, Steven J. Gallinger, Marc J. Gunter, Akihisa Hidaka, Michael Hoffmeister, Li Hsu, Mark A. Jenkins, Roger L. Milne, Victor Moreno, Polly A. Newcomb, Reiko Nishihara, Rish K. Pai, Lori C. Sakoda, Martha L. Slattery, Wei Sun, Efrat L. Amitay, Elizabeth Alwers, Stephen N. Thibodeau, Amanda E. Toland, Bethany Van Guelpen, Michael O. Woods, Syed H. Zaidi, John D. Potter, Marios Giannakis, Mingyang Song, Jonathan A. Nowak, Amanda I. Phipps, Ulrike Peters, and Shuji Ogino

Subjects
Hepatology, Gastroenterology
Published
2022

7. Supplementary Grant Support from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar

Abstract

Supplementary Grant Support

Published
2023

8. Supplementary Methods, Figures S1 - S3 from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar

Abstract

Supplementary Figure S1. LocusZoom regional association plots for the seven new cross-cancer loci that were > 1 Mb from known index SNPs. Supplementary Figure S2A-B. Box plots showing eQTL associations between (A) rs9375701 and L3MBTL3 in normal breast and prostate tissues and (B) rs8037137 and RCCD1 in normal breast and ovarian tissues. Supplementary Figure S3. Interactions between BCL2L11 and the 32 Biocarta "Death Pathway" genes. Interactions were identified using the GeneMania server. Circles contain gene names, lines represent interactions, and the color of the line indicates a specific type of interaction as listed in the legend.

Published
2023

9. Supplementary Tables S1 - S10 from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar

Abstract

Supplementary Table S1. Known risk loci for each cancer. Supplementary Table S2. Regions where known index SNPs for at least two of the three cancers lie within 1 Mb of each other. Supplementary Table S3. Full results from the meta-analysis of breast, ovarian, and prostate cancer showing the 18 independent loci associated at P < 10-8 with the same direction of effect across all three cancers. Supplementary Table S4. Conditional analysis of the rs1469713 (breast-ovarian-prostate cancer) signal, conditioning on the rs4808801 (breast cancer-specific) signal that was < 1 Mb away using GCTA software. Supplementary Table S5. Most significantly-associated genotyped SNP at new loci where index SNPs were imputed. Supplementary Table S6. Expression QTL analysis results from the GTEx Portal for the new cross-cancer risk loci listed in main Table 2. Supplementary Table S7. SNPs with P < 10-8 at the new cross-cancer risk loci listed in main Table 2 that overlap predicted enhancers in at least two cell types. Supplementary Table S8. HaploReg and non-coding RNA annotation of variants with P < 10-8 at the new cross-cancer risk loci listed in main Table 2. Supplementary Table S9. Eight of the 32 genes involved in induction of apoptosis through DR3 and DR4/5 Death Receptors (MSigDB: Biocarta "Death Pathway") a that were < 1 Mb away from an independent P < 10-5 index SNP in the 3-cancer meta-analysis. Supplementary Table S10. INRICH pathway analysis results for pathways with empirical P < 0.05. Apoptosis-related pathways containing BCL2L11 are shaded.

Published
2023

10. Tables S1-S3 from Quantifying the Genetic Correlation between Multiple Cancer Types

Author

Peter Kraft, Alkes L. Price, Benjamin Neale, David J. Hunter, Christopher A. Haiman, Douglas Easton, Rosalind Eeles, Sonja Berndt, Andrew Chan, Jenny Chang-Claude, Jeroen R. Huyghe, Li Hsu, Brian Wolpin, Harvey Risch, Gloria Petersen, Alison Klein, Rachael Stolzenberg-Solomon, Laufey T. Amundadottir, Thomas A. Sellers, Ellen L. Goode, Hui-Yi Lin, Jennifer B. Permuth, David Conti, Stephen B. Gruber, Kristin Rand, Rayjean J. Hung, Christopher I. Amos, Fredrick R. Schumacher, Brendan Bulik-Sullivan, Hilary Finucane, and Sara Lindström

Abstract

Supplementary Table S1: Non-cancer diseases and traits included in the analysis and source of summary statistics Supplementary Table S2. Cancer-specific cumulative risks from SEER. Supplementary Table S3: Genetic correlations between cancers and 14 non-cancer traits

Published
2023

11. Supplementary Material 1 from A Pooled Analysis of Smoking and Colorectal Cancer: Timing of Exposure and Interactions with Environmental Factors

Author

Ulrike Peters, John Potter, Emily White, Greg Warnick, Fridtjof Thomas, Deanna Stelling, Martha L. Slattery, Daniela Seminara, Robert Schoen, Thomas Rohan, Amanda I. Phipps, Bethann Pflugeisen, Polly Newcomb, Noralane M. Lindor, Yi Lin, Shuo Jiao, Li Hsu, Richard Hayes, Tabitha Harrison, Edward Giovannucci, Steven Gallinger, Charles S. Fuchs, Michelle Cotterchio, Andrew T. Chan, Graham Casey, Peter T. Campbell, Bette Caan, Sonja Berndt, John A. Baron, Carolyn Hutter, and Jian Gong

Abstract

PDF file - 59K, The description of studies included in this pooled analysis

Published
2023

12. Data from Quantifying the Genetic Correlation between Multiple Cancer Types

Author

Peter Kraft, Alkes L. Price, Benjamin Neale, David J. Hunter, Christopher A. Haiman, Douglas Easton, Rosalind Eeles, Sonja Berndt, Andrew Chan, Jenny Chang-Claude, Jeroen R. Huyghe, Li Hsu, Brian Wolpin, Harvey Risch, Gloria Petersen, Alison Klein, Rachael Stolzenberg-Solomon, Laufey T. Amundadottir, Thomas A. Sellers, Ellen L. Goode, Hui-Yi Lin, Jennifer B. Permuth, David Conti, Stephen B. Gruber, Kristin Rand, Rayjean J. Hung, Christopher I. Amos, Fredrick R. Schumacher, Brendan Bulik-Sullivan, Hilary Finucane, and Sara Lindström

Abstract

Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies.Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits.Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P < 0.003) genetic correlations between pancreatic and colorectal cancer (rg = 0.55, P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 × 10−6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer.Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors.Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis. Cancer Epidemiol Biomarkers Prev; 26(9); 1427–35. ©2017 AACR.

Published
2023

13. Data from A Pooled Analysis of Smoking and Colorectal Cancer: Timing of Exposure and Interactions with Environmental Factors

Author

Ulrike Peters, John Potter, Emily White, Greg Warnick, Fridtjof Thomas, Deanna Stelling, Martha L. Slattery, Daniela Seminara, Robert Schoen, Thomas Rohan, Amanda I. Phipps, Bethann Pflugeisen, Polly Newcomb, Noralane M. Lindor, Yi Lin, Shuo Jiao, Li Hsu, Richard Hayes, Tabitha Harrison, Edward Giovannucci, Steven Gallinger, Charles S. Fuchs, Michelle Cotterchio, Andrew T. Chan, Graham Casey, Peter T. Campbell, Bette Caan, Sonja Berndt, John A. Baron, Carolyn Hutter, and Jian Gong

Abstract

Background: Considerable evidence suggests that cigarette smoking is associated with a higher risk of colorectal cancer (CRC). What is unclear, however, is the impact of quitting smoking on risk attenuation and whether other risk factors for CRC modify this association.Methods: We conducted a pooled analysis of eight studies, including 6,796 CRC cases and 7,770 controls, to evaluate the association between cigarette smoking history and CRC risk and to investigate potential effect modification by other risk factors.Results: Current smokers [OR, 1.26; 95% confidence interval (CI), 1.11–1.43] and former smokers (OR, 1.18; 95% CI, 1.09–1.27), relative to never smokers, showed higher risks of CRC. Former smokers remained at higher CRC risk, relative to never smokers, for up to about 25 years after quitting. The impact of time since quitting varied by cancer subsite: The excess risk due to smoking decreased immediately after quitting for proximal colon and rectal cancer but not until about 20 years post-quitting for distal colon cancer. Furthermore, we observed borderline statistically significant additive interactions between smoking status and body mass index [BMI; relative excess risk due to interaction (RERI]), 0.15; 95% CI, −0.01 to 0.31; P = 0.06] and significant additive interaction between smoking status and fruit consumption (RERI, 0.16; 95% CI, 0.01–0.30; P = 0.04).Conclusion: CRC risk remained increased for about 25 years after quitting smoking, and the pattern of decline in risk varied by cancer subsite. BMI and fruit intake modified the risk associated with smoking.Impact: These results contribute to a better understanding of the mechanisms through which smoking impacts CRC etiology. Cancer Epidemiol Biomarkers Prev; 21(11); 1974–85. ©2012 AACR.

Published
2023

14. Supplementary Material 2 from A Pooled Analysis of Smoking and Colorectal Cancer: Timing of Exposure and Interactions with Environmental Factors

Author

Ulrike Peters, John Potter, Emily White, Greg Warnick, Fridtjof Thomas, Deanna Stelling, Martha L. Slattery, Daniela Seminara, Robert Schoen, Thomas Rohan, Amanda I. Phipps, Bethann Pflugeisen, Polly Newcomb, Noralane M. Lindor, Yi Lin, Shuo Jiao, Li Hsu, Richard Hayes, Tabitha Harrison, Edward Giovannucci, Steven Gallinger, Charles S. Fuchs, Michelle Cotterchio, Andrew T. Chan, Graham Casey, Peter T. Campbell, Bette Caan, Sonja Berndt, John A. Baron, Carolyn Hutter, and Jian Gong

Abstract

PDF file - 68K, The description of smoking variables included in this analysis

Published
2023

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

Author

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

Subjects
Global Nutrition, Wereldvoeding, Nutrition and Disease, Voeding en Ziekte, Genetics, Life Science, Article, VLAG
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. Cross-tissue analyses indicated that over a third of effector genes most likely 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.

Published
2023

18. 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

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

Subjects
Global Nutrition, Wereldvoeding, Nutrition and Disease, Voeding en Ziekte, Genetics, Life Science, VLAG
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

19. Abstract 1953: Association between genetic ancestry and all-cause mortality among Black and White ever-smokers in the PLCO cohort

Author

Courtney D. Dill, Dontray Crump, Rebecca Landy, Li C. Cheung, Wen-Yi Huang, Sonja Berndt, Neal Freedman, and Hormuzd Katki

Subjects
Cancer Research, Oncology
Abstract

Introduction: It is unknown how much of the increased all-cause mortality risk in Black individuals who ever-smoked is due to race as a social construct versus biological factors such as genetic ancestry. We examined the association of genetic ancestry with all-cause mortality, controlling for risk factors and self-reported race/ethnicity, in the PLCO cohort. Methods: We used PLCO data from 52,708 White individuals who ever-smoked (18281 deaths) and 2,585 Black individuals who ever-smoked (1108 deaths). Genetic ancestry was determined by GRAF (https://github.com/ncbi/graf) on a set of 10,000 pre-selected fingerprinting variants. Percent ancestry for each of Europe, Africa, and East-Asia was determined for each person. We fit Cox models for time to death, controlling for smoking history and other risk factors. Results: Self-reported Black individuals who ever-smoked had increased all-cause mortality versus self-reported White individuals who ever-smoked (HR=1.14, 95%CI: 1.07-1.22, p=0.00007). For White individuals, increases in European ancestry were associated with increased death risk, (HR=1.009 per 1% increase in European ancestry, 95%CI:1.003-1.015, p=0.002). HRs for European ancestry, by quartile, were 1.040, 1.061 and 1.063, with the last two HRs demonstrating statistical significance (95%CI:1.0018-1.106, p = 0.005, and 95%CI:1.020-1.108, p=0.004), respectively. For Black individuals, increases in African ancestry were associated with increased death risk, (HR=1.003 per 1% increase in African ancestry, 95%CI: 0.998-1.008, p=0.214), although not statistically significant. HRs for African ancestry, by quartile, were 1, 1.16, 1.14, and 1.21, with the last HR demonstrating statistical significance (95%CI:1.010-1.450, p = 0.03). Conclusions: For self-reported White individuals who ever-smoked, increasing European ancestry was associated with an increased all-cause mortality risk. For self-reported Black individuals who ever-smoked, there was suggestive evidence that increasing African ancestry may increase all-cause mortality risk. However, associations with ancestry were small and may be vulnerable to residual confounding. Impact/Significance: A mechanistic explanation for this finding is unclear, but it could be related to population genetic “fitness” with reduced genetic admixture leading to decreased fitness for survival. Citation Format: Courtney D. Dill, Dontray Crump, Rebecca Landy, Li C. Cheung, Wen-Yi Huang, Sonja Berndt, Neal Freedman, Hormuzd Katki. Association between genetic ancestry and all-cause mortality among Black and White ever-smokers in the PLCO cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1953.

Published
2023

20. Abstract PR011: Association of genetic ancestry with lung-cancer risk in White and Black ever-smokers

Author

Courtney D. Dill, Dontray Trump, Rebecca Landy, Li Cheung, Wen-Yi Huang, Sonja Berndt, Neal Freedman, and Hormuzd Katki

Subjects
Oncology, Epidemiology
Abstract

Introduction: Black smokers have higher lung cancer risk, and develop cancer at earlier ages, than White smokers. It is unknown how much of this excess risk is due to race as a social construct, and how much is due to biological factors such as genetic ancestry. We examine the association of genetic ancestry with lung-cancer risk, controlling for lung-cancer risk factors and self-reported race/ethnicity, in the PLCO cancer screening trial. Methods: We used PLCO data on ever-smokers from 52,708 White smokers (2889 lung cancers) and 2585 Black smokers (206 lung cancers) with genetic ancestry determined by GRAF (https://github.com/ncbi/graf) on a set of 10,000 pre-selected fingerprinting variants. Percent ancestry for each of Europe, Africa, and East-Asia was determined for each person. Because percent ancestry is strongly associated with self-reported race/ethnicity, we also standardized the ancestry variables to have mean=0 and variance=1 for each self-reported race/ethnicity, to isolate the potential biological effect of genetic ancestry from self-reported race/ethnicity as a social construct. Because European and African ancestry are negatively correlated, we considered European minus African ancestry (EMAA) and European ancestry. We fit Cox models for time to lung cancer diagnosis, controlling for smoking history and other lung-cancer risk factors. Results: Self-reported White smokers averaged 98.1% European ancestry (standard-deviation(𝜎)=2.8%) and 0.8% (𝜎=1.7%) African ancestry, while self-reported Black smokers averaged 22.0% (𝜎=14%) European ancestry and 75.8% (𝜎=14%) African ancestry. Controlling for smoking history and all lung-cancer risk factors, standardized European ancestry was associated with increased lung-cancer risk (HR=1.13 per 1 race/ethnicity-specific standard-deviation increase in European ancestry, 95%CI: 1.02-1.25, p=0.02) that is partly counteracted by increasing EMAA (HR=0.95, 95%CI: 0.90-1.003, p=0.06). In this model, self-reported Black smokers also had increased lung-cancer risk versus self-reported White smokers (HR=1.56, 95%CI: 1.35-1.80, p Citation Format: Courtney D. Dill, Dontray Trump, Rebecca Landy, Li Cheung, Wen-Yi Huang, Sonja Berndt, Neal Freedman, Hormuzd Katki. Association of genetic ancestry with lung-cancer risk in White and Black ever-smokers [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR011.

Published
2023

21. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author

Bjarni J. Vilhjálmsson, Jian Yang, Hilary K. Finucane, Alexander Gusev, Sara Lindström, Stephan Ripke, Giulio Genovese, Po-Ru Loh, Gaurav Bhatia, Ron Do, Tristan Hayeck, Hong-Hee Won, Sekar Kathiresan, Michele Pato, Carlos Pato, Rulla Tamimi, Eli Stahl, Noah Zaitlen, Bogdan Pasaniuc, Gillian Belbin, Eimear E. Kenny, Mikkel H. Schierup, Philip De Jager, Nikolaos A. Patsopoulos, Steve McCarroll, Mark Daly, Shaun Purcell, Daniel Chasman, Benjamin Neale, Michael Goddard, Peter M. Visscher, Peter Kraft, Nick Patterson, Alkes L. Price, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Lynn E. DeLisi, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Lyudmila Georgieva, Elliot S. Gershon, Ina Giegling, Paola Giusti-Rodrguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Jakob Grove, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julia, Rene S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, Brian J. Kelly, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kahler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lnnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Preben B. Mortensen, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Mller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietilinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Sderman, Srinivas Thirumalai, Draga Toncheva, Paul A. Tooney, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Jing Qin Wu, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tonu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jonsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Bryan J. Mowry, Markus M. Nthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St. Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, David J. Hunter, Muriel Adank, Habibul Ahsan, Kristiina Aittomäki, Laura Baglietto, Sonja Berndt, Carl Blomquist, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Laura Crisponi, Kamila Czene, Norbert Dahmen, Isabel dos Santos Silva, Douglas Easton, A. Heather Eliassen, Jonine Figueroa, Olivia Fletcher, Montserrat Garcia-Closas, Mia M. Gaudet, Lorna Gibson, Christopher A. Haiman, Per Hall, Aditi Hazra, Rebecca Hein, Brian E. Henderson, Albert Hofman, John L. Hopper, Astrid Irwanto, Mattias Johansson, Rudolf Kaaks, Muhammad G. Kibriya, Peter Lichtner, Eiliv Lund, Enes Makalic, Alfons Meindl, Hanne Meijers-Heijboer, Bertram Müller-Myhsok, Taru A. Muranen, Heli Nevanlinna, Petra H. Peeters, Julian Peto, Ross L. Prentice, Nazneen Rahman, María José Sánchez, Daniel F. Schmidt, Rita K. Schmutzler, Melissa C. Southey, Ruth Travis, Clare Turnbull, Andre G. Uitterlinden, Rob B. van der Luijt, Quinten Waisfisz, Zhaoming Wang, Alice S. Whittemore, Rose Yang, Wei Zheng, ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, Grove, Jakob, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Vilhjalmsson, Bjarni J, Yang, Jian, Finucane, Hilary K, Gusev, Alexander, Lee, SH, Price, Alkes L, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Study, Psychosis Endophenotype International Consortium, Wellcome Trust Case Control Consortium, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Human genetics, NCA - Brain mechanisms in health and disease, CCA - Oncogenesis, CCA - Quality of life, CCA - Cancer biology and immunology, Psychiatry, Department of Technology and Operations Management, Department of Organisation and Personnel Management, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Cell biology, and Internal Medicine

Subjects
Multifactorial Inheritance, Linkage disequilibrium, Complex disease, heritability, Bioinformatics, Medical and Health Sciences, Linkage Disequilibrium, 0302 clinical medicine, Theoretical, External reference, Models, Statistics, GWAS, Genetics(clinical), Genetics (clinical), Mathematics, Genetics & Heredity, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 0303 health sciences, Single Nucleotide, Biological Sciences, Serious Mental Illness, Prognosis, Thresholding, Regression, Mental Health, Phenotype, polygenic risk scores, Mixed model, Multiple Sclerosis, Genotype, Quantitative Trait Loci, polygenic risk score, schizophrenia, GWAS, Discovery, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetics, Humans, p-value, Pruning (decision trees), Polymorphism, Genome-Wide Association Study, Schizophrenia, Models, Theoretical, 030304 developmental biology, genome-wide association study, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Brain Disorders, Data set, schizophrenia, Sample size determination, polygenic risk score, Polygenic risk score, 030217 neurology & neurosurgery, linkage disequilibrium
Abstract

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R-2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. Refereed/Peer-reviewed

Published
2015

22. Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Author

Fangyi, Gu, Han, Zhang, Paula L, Hyland, Sonja, Berndt, Susan M, Gapstur, William, Wheeler, The, Ellipse Consortium, Christopher I, Amos, Stephane, Bezieau, Heike, Bickeböller, Hermann, Brenner, Paul, Brennan, Jenny, Chang-Claude, David V, Conti, Jennifer Anne, Doherty, Stephen B, Gruber, Tabitha A, Harrison, Richard B, Hayes, Michael, Hoffmeister, Richard S, Houlston, Rayjean J, Hung, Mark A, Jenkins, Peter, Kraft, Kate, Lawrenson, James, McKay, Sarah, Markt, Lorelei, Mucci, Catherine M, Phelan, Conghui, Qu, Angela, Risch, Mary Anne, Rossing, H-Erich, Wichmann, Jianxin, Shi, Eva, Schernhammer, Kai, Yu, Maria Teresa, Landi, Neil E, Caporaso, and Apollo - University of Cambridge Repository

Subjects
circadian rhythm, Male, Ovarian Neoplasms, Lung Neoplasms, Carcinogenesis, Cancer, Circadian Rhythm, Melatonin, Prostate Cancer, education, Prostatic Neoplasms, melatonin, Nerve Tissue Proteins, prostate cancer, Arylalkylamine N-Acetyltransferase, Polymorphism, Single Nucleotide, Article, Basic Helix-Loop-Helix Transcription Factors, cancer, Humans, Female, Genetic Predisposition to Disease, Colorectal Neoplasms, health care economics and organizations, Genetic Association Studies, Signal Transduction
Abstract

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (p pathway < 0.00625). The two most significant genes were NPAS2 (p gene =0.0062) and AANAT (p gene =0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (p pathway =0.021); this association was not confirmed in GECCO (p pathway =0.76) or the combined data (p pathway =0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.

Published
2017

23. Abstract 050: Meta-analysis of Genetic Associations in up to 339,224 Individuals Identify 66 New Loci for Bmi, Confirming a Neuronal Contribution to Body Weight Regulation and Implicating Several Novel Pathways

Author

Anne Justice, Kari North, Ruth Loos, Sailaja Vedantam, Felix Day, Sonja Berndt, Stefan Gustafsson, Adam Locke, Corey Powell, Kahali Bratati, Damien Croteau-Chonka, Thomas Winkler, Andre Scherag, Inês Barroso, Jacqui Beckmann, Cecilia Lindgren, Tune Pers, Peter Visscher, Cristen Willer, Jian Yang, Karen Mohlke, Joel Hirschorn, Erik Ingelsson, Michael Boehnke, and Elizabeth Speliotes

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

Obesity is a rising global concern as it substantially contributes to cardiovascular disease (CVD) and CVD risk factors (e.g. insulin resistance, dyslipidemia, Type 2 Diabetes). BMI (body mass index) is an easily obtained measure of obesity, which is highly heritable, and often used as a proxy when searching for genetic risk factors. Previous analyses of genome-wide association studies (GWAS) in the GIANT (Genetic Investigation of ANthropometric Traits) Consortium identified 32 loci containing common variants associated with BMI in adults of European ancestry. To enhance discovery of common causal variants for BMI, GIANT has expanded to include 82 studies with GWAS data and 43 studies with Metabochip data in more ancestrally diverse populations including up to 339,224 individuals. We performed a meta-analysis of the study-specific summary statistics for the BMI associations, assuming an additive model and using a fixed-effects inverse variance method. SNPs in 97 loci reached genome-wide significance (PMC4R, POMC, GRID1, NAV1 ). Our analyses also highlight loci with genes in pathways that were previously less apparent, such as those related to glucose and insulin homeostasis ( TCF7L2 , GIPR ), lipid metabolism ( APOE -cluster, NPC1 , NR1H3 ), the immune system ( TLR4) , and others. Additionally, many of the newly associated variants are in high LD with previously identified SNPs associated with related phenotypes, including other CVD risk factors (e.g. SNPs nearby IRS1 associated with T2D, adiposity, HDL, TG, adiponectin levels, and CHD; and SNPs near NT5C2 associated with CHD and blood pressure variables). This large-scale meta-analysis has greatly increased the number of identified obesity-susceptibility loci and continues to contribute to our understanding of the complex biology of adiposity. Our results have highlighted overlapping GWAS signals and important pathways which connect BMI and other CVD risk factors supporting the importance of pleiotropic effects in the pathogenesis of common complex diseases.

Published
2013

25. Improved Imputation of Common and Uncommon Single Nucleotide Polymorphisms (SNPs) with a New Reference Set

Author

Stephen Chanock, Nilanjan Chatterjee, Lauren Teras, Demetrius Albanes, Christopher Haiman, Sonja Berndt, Brian Henderson, W. Ryan Diver, Daniel Stram, Ann Hsing, Zhaoming Wang, Michael Eberle, Kevin Jacobs, Jennifer Stone, Meredith Yeager, Mark Purdue, Amy Hutchinson, Phil Taylor, Margaret Tucker, Xiang Deng, Susan Gabstur, and Joshua Sampson

Subjects
General Materials Science
Published
2011

26. Abstract 3863: Fine mapping and comprehensive resequencing analysis of a region of chromosome 11q13 reveals multiple independent loci associated with prostate cancer

Author

Chung, Charles C., primary, Ciampa, Julia, additional, Yeager, Meredith, additional, Jacobs, Kevin B., additional, Hayes, Richard B., additional, Deng, Zuoming, additional, Gonzalez-Bosquet, Jesus, additional, Kraft, Peter, additional, Sonja, Berndt I., additional, Sholom, Wacholder, additional, Orr, Nick, additional, Yu, Kai, additional, Hutchinson, Amy, additional, Feigelson, Heather Spencer, additional, Thun, Michael J., additional, Diver, W. Ryan, additional, Albanes, Demetrius, additional, Virtamo, Jarmo, additional, Weinstein, Stephanie, additional, Schumacher, Fredrick R., additional, Cancel-Tassin, Geraldine, additional, Cussenot, Olivier, additional, Valeri, Antoine, additional, Andriole, Gerald L., additional, Crawford, E. David, additional, Haiman, Christopher A., additional, Henderson, Brian E., additional, Kolonel, Laurence, additional, Marchand, Loic Le, additional, Siddiq, Afshan, additional, Riboli, Elio, additional, Key, Tim J., additional, Kaaks, Rudolf, additional, Isaacs, William B., additional, Isaacs, Sarah D., additional, Grönberg, Henrik, additional, Wiklund, Fredrik, additional, Xu, Jianfeng, additional, Vatten, Lars J., additional, Hveem, Kristian, additional, Kumle, Merethe, additional, Tucker, Margaret, additional, Hoover, Robert N., additional, Fraumeni, Joseph F., additional, Hunter, David J., additional, Thomas, Gilles, additional, Chatterjee, Nilanjan, additional, and Chanock, Stephen J., additional

Published
2010
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27. Abstract 1895: Genetic polymorphisms of an innate immune gene, Toll-Like Receptor 4, and aggressive prostate cancer risk: A systematic review and meta-analysis

Author

Jianfeng Xu, Sonja Berndt, Jen-Hau Chen, Yen-Ling Lin, Yen-Ching Chen, John S. Witte, Stephen J. Chanock, Stella Koutros, Yi-Ling Huang, and John H. Page

Subjects
Cancer Research, Toll-like receptor, business.industry, Odds ratio, Bioinformatics, medicine.disease, Prostate cancer, Immune system, Oncology, Meta-analysis, Genetic model, Genotype, Medicine, business, Genetic association
Abstract

Toll-like receptor 4 (TLR4) is located on the surface of macrophages and is important for the immune response to several pathogens. Chronic inflammation has been implicated in the pathogenesis of prostate cancer (PCa), and genetic polymorphisms of the innate immune gene TLR4 have been related to the risk of PCa. Six studies have explored the association between TLR4 polymorphisms and the risk of PCa. Five studies mainly included men of European ancestry. We conducted a systematic review of all genetic association studies that evaluated the relationship between TLR4 genotypes and aggressive PCa risk. We found the rs11536889 variant was significantly associated with an increased risk of aggressive PCa under a dominant genetic model [odds ratio (OR) = 1.20, 95% CI = 1.05-1.37]. However, rs1927914, rs2149356, or rs10759932 polymorphisms were not associated with the risk of PCa under any inheritance mode. In conclusion, this study found that the polymorphism TLR4 rs11536889 was significantly associated with the risk of aggressive PCa. Additional large-scale genetic association studies are needed to confirm these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1895. doi:10.1158/1538-7445.AM2011-1895

Published
2011

28. Abstract B129: Xenobiotic metabolizing genes, meat intake and risk of advanced colorectal adenoma

Author

Marc J. Gunter, Rashmi Sinha, Meredith Yeager, Xiaomei Ma, Barry Graubard, Sonja Berndt, Amanda Cross, Stephen Chanock, Susan Mayne, Jiyoung Ahn, Richard Hayes, Wen-Yi Huang, and Leah Ferrucci

Subjects
Genetics, Cancer Research, medicine.medical_specialty, Cancer prevention, business.industry, Cancer, Single-nucleotide polymorphism, EPHX1, Colorectal adenoma, medicine.disease, Gastroenterology, Oncology, Internal medicine, Red meat, Medicine, business, CYP2A6, Carcinogen
Abstract

B129 Red meat and processed meat are positively associated with risk of colorectal neoplasia. One of the potential mechanisms underlying the association of meat with cancer is via the mutagenic action of heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) formed during high temperature cooking. Phase I xenobiotic metabolizing enzymes (XMEs) are involved in the initial steps of activation of xenobiotics to mutagenic and carcinogenic intermediates. Phase II XMEs convert original xenobiotic compounds and their phase I-activated metabolites to polar and detoxified metabolites. However, with certain compounds, such as HCAs, phase II XMEs may further activate metabolites to form other carcinogenic species. We evaluated 29 single nucleotide polymorphisms (SNPs) in several phase I (CYP1A1, CYP1B1, CYP2A6, CYP2C9, CYP2E1, and CYP3A4) and phase II (EPHX1, GSTM1, GSTM2, GSTT1, NAT1, NAT2, NQO1, SULT1A1, and SULT1A2) XME genes in relation to advanced colorectal adenoma and investigated potential effect modification by red meat, HCA, and PAH intake. All SNPS were selected based on known or suggested functional relevance and a minor allele frequency of 5% or greater in Caucasians. Participants were selected from individuals who were enrolled in the screening arm (n = 77,483) of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial between 1993 and 1999. We compared 720 cases with advanced colorectal adenoma (size of 1cm or greater, high grade dysplasia, or villous components, including tubulovillous) of the distal colon or rectum to 746 controls frequency matched on gender and ethnicity (negative for left-sided polyp by sigmoidoscopy). Using a 137-item food frequency questionnaire that included detailed questions on meat cooking methods and doneness levels in conjunction with a HCA and PAH database, we generated intake estimates of the HCAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP), and the PAH, benzo[a]pyrene (B[a]P) in ng/day. Odd ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age, gender, and ethnicity. Tests for interaction were based on the likelihood ratio test by comparing models with and without interaction terms. Overall, we found weak or null associations between the individual XME genes or SNPs with risk of advanced colorectal adenoma. However, we observed interactions between intake of PhIP and variation in CYP1B1 (rs10012 Pinteraction = 0.019; rs1056836 Pinteraction = 0.019), and NQO1 (rs1800566 Pinteraction = 0.007) with advanced colorectal adenoma. We also found evidence of interaction with intake of B[a]P for variation in CYP1B1 (rs10012 Pinteraction = 0.005) and CYP3A4 (rs2242480 Pinteraction = 0.02). In addition, there was an interaction with intake of red meat and CYP1B1 (rs10012 Pinteraction = 0.013) and NAT1 variants (rs15561 Pinteraction = 0.037). However, when considering multiple comparisons, these interactions did not fall below a false discovery rate threshold of 0.20. Our results are intriguing and suggest that common variants in XME genes may modify the association of red meat, HCA, and PAH intake with advanced colorectal adenoma, but require confirmation in larger studies. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B129.

Published
2008

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