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1. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author

Alison P. Klein, Brian M. Wolpin, Harvey A. Risch, Rachael Z. Stolzenberg-Solomon, Evelina Mocci, Mingfeng Zhang, Federico Canzian, Erica J. Childs, Jason W. Hoskins, Ashley Jermusyk, Jun Zhong, Fei Chen, Demetrius Albanes, Gabriella Andreotti, Alan A. Arslan, Ana Babic, William R. Bamlet, Laura Beane-Freeman, Sonja I. Berndt, Amanda Blackford, Michael Borges, Ayelet Borgida, Paige M. Bracci, Lauren Brais, Paul Brennan, Hermann Brenner, Bas Bueno-de-Mesquita, Julie Buring, Daniele Campa, Gabriele Capurso, Giulia Martina Cavestro, Kari G. Chaffee, Charles C. Chung, Sean Cleary, Michelle Cotterchio, Frederike Dijk, Eric J. Duell, Lenka Foretova, Charles Fuchs, Niccola Funel, Steven Gallinger, J. Michael M. Gaziano, Maria Gazouli, Graham G. Giles, Edward Giovannucci, Michael Goggins, Gary E. Goodman, Phyllis J. Goodman, Thilo Hackert, Christopher Haiman, Patricia Hartge, Manal Hasan, Peter Hegyi, Kathy J. Helzlsouer, Joseph Herman, Ivana Holcatova, Elizabeth A. Holly, Robert Hoover, Rayjean J. Hung, Eric J. Jacobs, Krzysztof Jamroziak, Vladimir Janout, Rudolf Kaaks, Kay-Tee Khaw, Eric A. Klein, Manolis Kogevinas, Charles Kooperberg, Matthew H. Kulke, Juozas Kupcinskas, Robert J. Kurtz, Daniel Laheru, Stefano Landi, Rita T. Lawlor, I.-Min Lee, Loic LeMarchand, Lingeng Lu, Núria Malats, Andrea Mambrini, Satu Mannisto, Roger L. Milne, Beatrice Mohelníková-Duchoňová, Rachel E. Neale, John P. Neoptolemos, Ann L. Oberg, Sara H. Olson, Irene Orlow, Claudio Pasquali, Alpa V. Patel, Ulrike Peters, Raffaele Pezzilli, Miquel Porta, Francisco X. Real, Nathaniel Rothman, Ghislaine Scelo, Howard D. Sesso, Gianluca Severi, Xiao-Ou Shu, Debra Silverman, Jill P. Smith, Pavel Soucek, Malin Sund, Renata Talar-Wojnarowska, Francesca Tavano, Mark D. Thornquist, Geoffrey S. Tobias, Stephen K. Van Den Eeden, Yogesh Vashist, Kala Visvanathan, Pavel Vodicka, Jean Wactawski-Wende, Zhaoming Wang, Nicolas Wentzensen, Emily White, Herbert Yu, Kai Yu, Anne Zeleniuch-Jacquotte, Wei Zheng, Peter Kraft, Donghui Li, Stephen Chanock, Ofure Obazee, Gloria M. Petersen, and Laufey T. Amundadottir

Subjects
Science
Abstract

Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.

Published
2018
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2. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Author

Philip J. Law, Sonja I. Berndt, Helen E. Speedy, Nicola J. Camp, Georgina P. Sava, Christine F. Skibola, Amy Holroyd, Vijai Joseph, Nicola J. Sunter, Alexandra Nieters, Silvia Bea, Alain Monnereau, David Martin-Garcia, Lynn R. Goldin, Guillem Clot, Lauren R. Teras, Inés Quintela, Brenda M. Birmann, Sandrine Jayne, Wendy Cozen, Aneela Majid, Karin E. Smedby, Qing Lan, Claire Dearden, Angela R. Brooks-Wilson, Andrew G. Hall, Mark P. Purdue, Tryfonia Mainou-Fowler, Claire M. Vajdic, Graham H. Jackson, Pierluigi Cocco, Helen Marr, Yawei Zhang, Tongzhang Zheng, Graham G. Giles, Charles Lawrence, Timothy G. Call, Mark Liebow, Mads Melbye, Bengt Glimelius, Larry Mansouri, Martha Glenn, Karen Curtin, W Ryan Diver, Brian K. Link, Lucia Conde, Paige M. Bracci, Elizabeth A. Holly, Rebecca D. Jackson, Lesley F. Tinker, Yolanda Benavente, Paolo Boffetta, Paul Brennan, Marc Maynadie, James McKay, Demetrius Albanes, Stephanie Weinstein, Zhaoming Wang, Neil E. Caporaso, Lindsay M. Morton, Richard K. Severson, Elio Riboli, Paolo Vineis, Roel C. H. Vermeulen, Melissa C. Southey, Roger L. Milne, Jacqueline Clavel, Sabine Topka, John J. Spinelli, Peter Kraft, Maria Grazia Ennas, Geoffrey Summerfield, Giovanni M. Ferri, Robert J. Harris, Lucia Miligi, Andrew R. Pettitt, Kari E. North, David J. Allsup, Joseph F. Fraumeni, James R. Bailey, Kenneth Offit, Guy Pratt, Henrik Hjalgrim, Chris Pepper, Stephen J. Chanock, Chris Fegan, Richard Rosenquist, Silvia de Sanjose, Angel Carracedo, Martin J. S. Dyer, Daniel Catovsky, Elias Campo, James R. Cerhan, James M. Allan, Nathanial Rothman, Richard Houlston, and Susan Slager

Subjects
Science
Abstract

Chronic lymphocytic leukaemia has a hereditary component, much of which remains to be identified. Here, the authors perform a genome-wide association study and find new risk loci for the disease, which are associated with genes involved in immune function.

Published
2017
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3. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

Author

Mitchell J. Machiela, Weiyin Zhou, Eric Karlins, Joshua N. Sampson, Neal D. Freedman, Qi Yang, Belynda Hicks, Casey Dagnall, Christopher Hautman, Kevin B. Jacobs, Christian C. Abnet, Melinda C. Aldrich, Christopher Amos, Laufey T. Amundadottir, Alan A. Arslan, Laura E. Beane-Freeman, Sonja I. Berndt, Amanda Black, William J. Blot, Cathryn H. Bock, Paige M. Bracci, Louise A. Brinton, H Bas Bueno-de-Mesquita, Laurie Burdett, Julie E. Buring, Mary A. Butler, Federico Canzian, Tania Carreón, Kari G. Chaffee, I-Shou Chang, Nilanjan Chatterjee, Chu Chen, Constance Chen, Kexin Chen, Charles C. Chung, Linda S. Cook, Marta Crous Bou, Michael Cullen, Faith G. Davis, Immaculata De Vivo, Ti Ding, Jennifer Doherty, Eric J. Duell, Caroline G. Epstein, Jin-Hu Fan, Jonine D. Figueroa, Joseph F. Fraumeni, Christine M. Friedenreich, Charles S. Fuchs, Steven Gallinger, Yu-Tang Gao, Susan M. Gapstur, Montserrat Garcia-Closas, Mia M. Gaudet, J. Michael Gaziano, Graham G. Giles, Elizabeth M. Gillanders, Edward L. Giovannucci, Lynn Goldin, Alisa M. Goldstein, Christopher A. Haiman, Goran Hallmans, Susan E. Hankinson, Curtis C. Harris, Roger Henriksson, Elizabeth A. Holly, Yun-Chul Hong, Robert N. Hoover, Chao A. Hsiung, Nan Hu, Wei Hu, David J. Hunter, Amy Hutchinson, Mazda Jenab, Christoffer Johansen, Kay-Tee Khaw, Hee Nam Kim, Yeul Hong Kim, Young Tae Kim, Alison P. Klein, Robert Klein, Woon-Puay Koh, Laurence N. Kolonel, Charles Kooperberg, Peter Kraft, Vittorio Krogh, Robert C. Kurtz, Andrea LaCroix, Qing Lan, Maria Teresa Landi, Loic Le Marchand, Donghui Li, Xiaolin Liang, Linda M. Liao, Dongxin Lin, Jianjun Liu, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Nuria Malats, Keitaro Matsuo, Lorna H. McNeill, Robert R. McWilliams, Beatrice S. Melin, Lisa Mirabello, Lee Moore, Sara H. Olson, Irene Orlow, Jae Yong Park, Ana Patiño-Garcia, Beata Peplonska, Ulrike Peters, Gloria M. Petersen, Loreall Pooler, Jennifer Prescott, Ludmila Prokunina-Olsson, Mark P. Purdue, You-Lin Qiao, Preetha Rajaraman, Francisco X. Real, Elio Riboli, Harvey A. Risch, Benjamin Rodriguez-Santiago, Avima M. Ruder, Sharon A. Savage, Fredrick Schumacher, Ann G. Schwartz, Kendra L. Schwartz, Adeline Seow, Veronica Wendy Setiawan, Gianluca Severi, Hongbing Shen, Xin Sheng, Min-Ho Shin, Xiao-Ou Shu, Debra T. Silverman, Margaret R. Spitz, Victoria L. Stevens, Rachael Stolzenberg-Solomon, Daniel Stram, Ze-Zhong Tang, Philip R. Taylor, Lauren R. Teras, Geoffrey S. Tobias, David Van Den Berg, Kala Visvanathan, Sholom Wacholder, Jiu-Cun Wang, Zhaoming Wang, Nicolas Wentzensen, William Wheeler, Emily White, John K. Wiencke, Brian M. Wolpin, Maria Pik Wong, Chen Wu, Tangchun Wu, Xifeng Wu, Yi-Long Wu, Jay S. Wunder, Lucy Xia, Hannah P. Yang, Pan-Chyr Yang, Kai Yu, Krista A. Zanetti, Anne Zeleniuch-Jacquotte, Wei Zheng, Baosen Zhou, Regina G. Ziegler, Luis A. Perez-Jurado, Neil E. Caporaso, Nathaniel Rothman, Margaret Tucker, Michael C. Dean, Meredith Yeager, and Stephen J. Chanock

Subjects
Science
Abstract

It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk

Published
2016
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4. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

Author

Sonja I. Berndt, Nicola J. Camp, Christine F. Skibola, Joseph Vijai, Zhaoming Wang, Jian Gu, Alexandra Nieters, Rachel S. Kelly, Karin E. Smedby, Alain Monnereau, Wendy Cozen, Angela Cox, Sophia S. Wang, Qing Lan, Lauren R. Teras, Moara Machado, Meredith Yeager, Angela R. Brooks-Wilson, Patricia Hartge, Mark P. Purdue, Brenda M. Birmann, Claire M. Vajdic, Pierluigi Cocco, Yawei Zhang, Graham G. Giles, Anne Zeleniuch-Jacquotte, Charles Lawrence, Rebecca Montalvan, Laurie Burdett, Amy Hutchinson, Yuanqing Ye, Timothy G. Call, Tait D. Shanafelt, Anne J. Novak, Neil E. Kay, Mark Liebow, Julie M. Cunningham, Cristine Allmer, Henrik Hjalgrim, Hans-Olov Adami, Mads Melbye, Bengt Glimelius, Ellen T. Chang, Martha Glenn, Karen Curtin, Lisa A. Cannon-Albright, W Ryan Diver, Brian K. Link, George J. Weiner, Lucia Conde, Paige M. Bracci, Jacques Riby, Donna K. Arnett, Degui Zhi, Justin M. Leach, Elizabeth A. Holly, Rebecca D. Jackson, Lesley F. Tinker, Yolanda Benavente, Núria Sala, Delphine Casabonne, Nikolaus Becker, Paolo Boffetta, Paul Brennan, Lenka Foretova, Marc Maynadie, James McKay, Anthony Staines, Kari G. Chaffee, Sara J. Achenbach, Celine M. Vachon, Lynn R. Goldin, Sara S. Strom, Jose F. Leis, J. Brice Weinberg, Neil E. Caporaso, Aaron D. Norman, Anneclaire J. De Roos, Lindsay M. Morton, Richard K. Severson, Elio Riboli, Paolo Vineis, Rudolph Kaaks, Giovanna Masala, Elisabete Weiderpass, María- Dolores Chirlaque, Roel C. H. Vermeulen, Ruth C. Travis, Melissa C. Southey, Roger L. Milne, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Jacqueline Clavel, Tongzhang Zheng, Theodore R. Holford, Danylo J. Villano, Ann Maria, John J. Spinelli, Randy D. Gascoyne, Joseph M. Connors, Kimberly A. Bertrand, Edward Giovannucci, Peter Kraft, Anne Kricker, Jenny Turner, Maria Grazia Ennas, Giovanni M. Ferri, Lucia Miligi, Liming Liang, Baoshan Ma, Jinyan Huang, Simon Crouch, Ju-Hyun Park, Nilanjan Chatterjee, Kari E. North, John A. Snowden, Josh Wright, Joseph F. Fraumeni, Kenneth Offit, Xifeng Wu, Silvia de Sanjose, James R. Cerhan, Stephen J. Chanock, Nathaniel Rothman, and Susan L. Slager

Subjects
Science
Abstract

Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPPassociated with risk of this disease.

Published
2016
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5. Distributed processing for value-based choice by prelimbic circuits targeting anterior-posterior dorsal striatal subregions in male mice

Author

Kyuhyun Choi, Eugenio Piasini, Edgar Díaz-Hernández, Luigim Vargas Cifuentes, Nathan T. Henderson, Elizabeth N. Holly, Manivannan Subramaniyan, Charles R. Gerfen, and Marc V. Fuccillo

Subjects
Science
Abstract

The prelimbic region of the prefrontal cortex is involved in goal-directed action. Here the authors investigate the function of the prelimbic pathways projecting along the anterior posterior striatal axis in value based decision making in male mice.

Published
2023
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6. Physical activity and the risk of <scp>non‐Hodgkin</scp> lymphoma subtypes: A pooled analysis

Author

Terry Boyle, Geffen Kleinstern, Paige M. Bracci, James R. Cerhan, Yolanda Benavente, Delphine Casabonne, Brian C.‐H. Chiu, Thomas M. Habermann, Elizabeth A. Holly, Mark Liebow, Aaron Norman, Ora Paltiel, Dennis Robinson, Nathaniel Rothman, Rania Abu Seir, Susan L. Slager, Paul J. Villeneuve, Sophia S. Wang, Dennis D. Weisenburger, John J. Spinelli, Boyle, Terry, Kleinstern, Geffen, Bracci, Paige M, Cerhan, James R, Benavente, Yolanda, Casabonne, Delphine, Chiu, Brian C-H, Habermann, Thomas M, Holly, Elizabeth A, Liebow, Mark, Norman, Aaron, Paltiel, Ora, Robinson, Dennis, Rothman, Nathaniel, Abu Seir, Rania, Slager, Susan L, Villeneuve, Paul J, Wang, Sophia S, Weisenburger, Dennis D, and Spinelli, John J

Subjects
Cancer Research, Oncology, non-Hodgkin lymphoma, physical activity, epidemiology
Abstract

Non-Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case-control studies to examine the association between moderate-to-vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T-cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study-specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case-control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL. Refereed/Peer-reviewed

Published
2022

7. Supplementary Data from Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Author

Rachael Stolzenberg-Solomon, Alison P. Klein, Nilanjan Chatterjee, Peter Kraft, Harvey A. Risch, Brian M. Wolpin, Gloria M. Petersen, Eric J. Jacobs, Donghui Li, Laufey T. Amundadottir, Anne Zeleniuch-Jacquotte, Fangcheng Yuan, Herbert Yu, Lynne R. Wilkens, Nicolas Wentzensen, Jean Wactawski-Wende, Stephen K. Van Den Eeden, Antonia Trichopoulou, Anne Tjonneland, Ian M. Thompson, Oliver Strobel, Victoria L. Stevens, Debra T. Silverman, Howard D. Sesso, Ghislaine Scelo, Nathaniel Rothman, Elio Riboli, Kari G. Rabe, Miquel Porta, Ulrike Peters, Salvatore Panico, Ann L. Oberg, Kimmie Ng, Roger L. Milne, Núria Malats, I-Min Lee, Robert C. Kurtz, Rayjean J. Hung, Robert N. Hoover, Elizabeth A. Holly, Manal M. Hassan, Patricia Hartge, Michael G. Goggins, Edward L. Giovannucci, J. Michael Gaziano, Charles S. Fuchs, Eric J. Duell, Erica J. Childs, Stephen J. Chanock, Daniele Campa, Julie E. Buring, Bas Bueno-de-Mesquita, Amanda L. Blackford, Sonja I. Berndt, William R. Bamlet, Ana Babic, Gabriella Andreotti, Demetrius Albanes, Wei Zheng, Emily White, Kala Visvanathan, Xiao-Ou Shu, Rachel E. Neale, Loic Le Marchand, Charles Kooperberg, Phyllis J. Goodman, Graham G. Giles, Steven Gallinger, Mengmeng Du, Federico Canzian, Paul Brennan, Paige M. Bracci, Laura E. Beane-Freeman, Alan A. Arslan, William Wheeler, Prosenjit Kundu, and Evelina Mocci

Abstract

Supplemental figures 1 and 2. Supplemental tables 1-7.

Published
2023

8. Supplementary Methods, Tables 1-5, Figures 1-4 from Development and Validation of a Melanoma Risk Score Based on Pooled Data from 16 Case–Control Studies

Author

Julia Newton-Bishop, Jennifer H. Barrett, Richard P. Gallagher, Andreas Ziegler, Michael S. Zens, Linda Titus, Anthony J. Swerdlow, Victor Siskind, Peter Sasieni, Kristian Reich, Timothy R. Rebbeck, Anne Østerlind, Håkan Olsson, Rona M. Mackie, Loïc Le Marchand, Tim K. Lee, Margaret R. Karagas, Peter A. Kanetsky, Christian Ingvar, Elizabeth A. Holly, Nelleke A. Gruis, Adele Green, Marc S. Ernstoff, J. Mark Elwood, Paige M. Bracci, Marianne Berwick, Wilma Bergman, Veronique Bataille, Bruce K. Armstrong, D. Timothy Bishop, Yu-mei Chang, and John R. Davies

Abstract

Supplementary Methods, Tables 1-5, Figures 1-4. Contains additional Methods and Materials on the coding of variables in the risk model, recruitment of cases to the Leeds Case-Control study, imputation, comparing self reported and nurse derived mole counts and calculations for estimating absolute risk. Contains Tables 1-5 on missingness of pooled data, risk assessment for the Leeds dataset including imputed cases, comparisons of self classification and nurse classification of mole count/freckling in the Leeds controls. Contains Figures 1-4 showing the distribution of risk scores in the pooled and Leeds data, a bland-altman plot comparing nurse and self assessment of mole count on the back in Leeds controls and a cartoon used in the Leeds Case-Control study to determine mole count.

Published
2023

9. Supplemental Table from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author

Christine F. Skibola, Patricia Hartge, Nathaniel Rothman, Stephen J. Chanock, Peter Kraft, Yawei Zhang, Anne Kricker, Eve Roman, Martyn T. Smith, Angela Brooks-Wilson, Qing Lan, Richard K. Severson, Scott Davis, Anthony Staines, Lenka Foretova, Paulo Bofetta, Gilles Salles, Hervé Ghesquières, David G. Cox, Alain Monnereau, Jacqueline Clavel, Karen Curtin, Martha Glenn, Nicola J. Camp, Lucia Conde, Bengt Glimelius, Mads Melbye, Hans-Olov Adami, Mark P. Purdue, Alan A. Arslan, Jacob Musinsky, Kenneth Offit, Roger L. Milne, Melissa C. Southey, Graham G. Giles, Nicole Wong Doo, Andrew L. Feldman, Giancarlo Latte, Maria Grazia Ennas, Corrado Magnani, Brian K. Link, Marie-Hélène Delfau-Larue, James McKay, Paul Brennan, Yolanda Benavente, Elio Riboli, Rudolph Kaaks, Ruth C. Travis, Stephanie J. Lax, W. Ryan Diver, Lauren R. Teras, Stephanie J. Weinstein, Demetrius Albanes, Pierluigi Cocco, Marc Maynadie, Dennis Weisenburger, Eleanor Kane, Elizabeth A. Holly, Nikolaus Becker, Christopher R. Flowers, Brenda M. Birmann, Tongzhang Zheng, John J. Spinelli, Jennifer Turner, Elizabeth E. Brown, Wendy Cozen, Silvia de Sanjose, Alexandra Nieters, Martha S. Linet, Claire M. Vajdic, Ora Paltiel, Roel Vermeulen, Lindsay M. Morton, Joseph Vijai, Henrik Hjalgrim, Karin E. Smedby, James R. Cerhan, Jenna Voutsinas, Paige M. Bracci, Susan L. Slager, Sonja I. Berndt, Mary Carrington, and Sophia S. Wang

Abstract

SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)

Published
2023

10. Data from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author

Christine F. Skibola, Patricia Hartge, Nathaniel Rothman, Stephen J. Chanock, Peter Kraft, Yawei Zhang, Anne Kricker, Eve Roman, Martyn T. Smith, Angela Brooks-Wilson, Qing Lan, Richard K. Severson, Scott Davis, Anthony Staines, Lenka Foretova, Paulo Bofetta, Gilles Salles, Hervé Ghesquières, David G. Cox, Alain Monnereau, Jacqueline Clavel, Karen Curtin, Martha Glenn, Nicola J. Camp, Lucia Conde, Bengt Glimelius, Mads Melbye, Hans-Olov Adami, Mark P. Purdue, Alan A. Arslan, Jacob Musinsky, Kenneth Offit, Roger L. Milne, Melissa C. Southey, Graham G. Giles, Nicole Wong Doo, Andrew L. Feldman, Giancarlo Latte, Maria Grazia Ennas, Corrado Magnani, Brian K. Link, Marie-Hélène Delfau-Larue, James McKay, Paul Brennan, Yolanda Benavente, Elio Riboli, Rudolph Kaaks, Ruth C. Travis, Stephanie J. Lax, W. Ryan Diver, Lauren R. Teras, Stephanie J. Weinstein, Demetrius Albanes, Pierluigi Cocco, Marc Maynadie, Dennis Weisenburger, Eleanor Kane, Elizabeth A. Holly, Nikolaus Becker, Christopher R. Flowers, Brenda M. Birmann, Tongzhang Zheng, John J. Spinelli, Jennifer Turner, Elizabeth E. Brown, Wendy Cozen, Silvia de Sanjose, Alexandra Nieters, Martha S. Linet, Claire M. Vajdic, Ora Paltiel, Roel Vermeulen, Lindsay M. Morton, Joseph Vijai, Henrik Hjalgrim, Karin E. Smedby, James R. Cerhan, Jenna Voutsinas, Paige M. Bracci, Susan L. Slager, Sonja I. Berndt, Mary Carrington, and Sophia S. Wang

Abstract

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Published
2023

11. Data from Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk

Author

Rachael Stolzenberg-Solomon, Alison P. Klein, Kai Yu, Harvey A. Risch, Brian M. Wolpin, Gloria M. Petersen, Donghui Li, Laufey T. Amundadottir, Eric J. Duell, Jianxin Shi, Anne Zeleniuch-Jacquotte, Herbert Yu, Lynne R. Wilkens, Nicolas Wentzensen, Xiaoliang Wang, Jean Wactawski-Wende, Ian M. Thompson, Debra T. Silverman, Howard D. Sesso, Nathaniel Rothman, Francisco X. Real, Kari G. Rabe, Miquel Porta, Ann L. Oberg, Kimmie Ng, Neil Murphy, Roger L. Milne, Nuria Malats, I-Min Lee, Robert C. Kurtz, Holger Kirsten, Verena Katzke, Robert N. Hoover, Elizabeth A. Holly, Manal M. Hassan, Patricia Hartge, Thilo Hackert, Michael G. Goggins, J. Michael Gaziano, Charles S. Fuchs, Stephen J. Chanock, Peter T. Campbell, Julie E. Buring, Bas Bueno-de-Mesquita, Paul Brennan, Sonja I. Berndt, William R. Bamlet, Ana Babic, Gabriella Andreotti, Pilar Amiano, Demetrius Albanes, Wei Zheng, Emily White, Kala Visvanathan, Xiao-Ou Shu, Ghislaine Scelo, Jonas Rosendahl, Rachel E. Neale, Loic Le Marchand, Charles Kooperberg, Phyllis J. Goodman, Graham G. Giles, Steven Gallinger, Mengmeng Du, Federico Canzian, Paige Bracci, Laura E. Beane Freeman, Alan A. Arslan, Lei Song, William Wheeler, Elizabeth A. Platz, Han Zhang, Naomi Walsh, Rayjean J. Hung, and Fangcheng Yuan

Abstract

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10−6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC.Significance:The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.

Published
2023

12. Supplementary Tables 1 and 2 from Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium

Author

Eve Roman, Tongzhang Zheng, Yawei Zhang, Sophia S. Wang, Susan L. Slager, Silvia de Sanjosé, Lindsay Morton, Mads Melbye, Mark Liebow, Alex G. Smith, Stephen M. Ansell, Tracy J. Lightfoot, Anne J. Novak, Marc Maynadié, Elizabeth A. Holly, Karin Ekström Smedby, Laura Costas, James R. Cerhan, Paige M. Bracci, Christine F. Skibola, and Eleanor Kane

Abstract

Supplementary Tables 1 and 2. Joint associations and relative excess risks due to interaction between BMI and cytokine polymorphisms for lymphoid neoplasms

Published
2023

13. Data from Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium

Author

Eve Roman, Tongzhang Zheng, Yawei Zhang, Sophia S. Wang, Susan L. Slager, Silvia de Sanjosé, Lindsay Morton, Mads Melbye, Mark Liebow, Alex G. Smith, Stephen M. Ansell, Tracy J. Lightfoot, Anne J. Novak, Marc Maynadié, Elizabeth A. Holly, Karin Ekström Smedby, Laura Costas, James R. Cerhan, Paige M. Bracci, Christine F. Skibola, and Eleanor Kane

Abstract

Background: Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms, and selected mature B-cell neoplasms is reported.Method: Data on 4,979 cases and 4,752 controls from nine American/European studies from the InterLymph consortium (1988–2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944, rs1143627), IL1RN (rs454078), IL2 (rs2069762), IL6 (rs1800795, rs1800797), IL10 (rs1800890, rs1800896), TNF (rs1800629), LTA (rs909253), and CARD15 (rs2066847) were investigated using unconditional logistic regression. BMI-polymorphism interaction effects were estimated using the relative excess risk due to interaction (RERI).Results: Obesity (BMI ≥ 30 kg/m2) was associated with DLBCL risk [OR = 1.33; 95% confidence interval (CI), 1.02–1.73], as was TNF-308GA+AA (OR = 1.24; 95% CI, 1.07–1.44). Together, being obese and TNF-308GA+AA increased DLBCL risk almost 2-fold relative to those of normal weight and TNF-308GG (OR = 1.93; 95% CI, 1.27–2.94), with a RERI of 0.41 (95% CI, −0.05–0.84; Pinteraction = 0.13). For FL and CLL/SLL, no associations with obesity or TNF-308GA+AA, either singly or jointly, were observed. No evidence of interactions between obesity and the other polymorphisms were detected.Conclusions: Our results suggest that cytokine polymorphisms do not generally interact with BMI to increase lymphoma risk but obesity and TNF-308GA+AA may interact to increase DLBCL risk.Impact: Studies using better measures of adiposity are needed to further investigate the interactions between obesity and TNF-308G>A in the pathogenesis of lymphoma. Cancer Epidemiol Biomarkers Prev; 24(7); 1061–70. ©2015 AACR.

Published
2023

14. Data from Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Author

Rachael Stolzenberg-Solomon, Alison P. Klein, Nilanjan Chatterjee, Peter Kraft, Harvey A. Risch, Brian M. Wolpin, Gloria M. Petersen, Eric J. Jacobs, Donghui Li, Laufey T. Amundadottir, Anne Zeleniuch-Jacquotte, Fangcheng Yuan, Herbert Yu, Lynne R. Wilkens, Nicolas Wentzensen, Jean Wactawski-Wende, Stephen K. Van Den Eeden, Antonia Trichopoulou, Anne Tjonneland, Ian M. Thompson, Oliver Strobel, Victoria L. Stevens, Debra T. Silverman, Howard D. Sesso, Ghislaine Scelo, Nathaniel Rothman, Elio Riboli, Kari G. Rabe, Miquel Porta, Ulrike Peters, Salvatore Panico, Ann L. Oberg, Kimmie Ng, Roger L. Milne, Núria Malats, I-Min Lee, Robert C. Kurtz, Rayjean J. Hung, Robert N. Hoover, Elizabeth A. Holly, Manal M. Hassan, Patricia Hartge, Michael G. Goggins, Edward L. Giovannucci, J. Michael Gaziano, Charles S. Fuchs, Eric J. Duell, Erica J. Childs, Stephen J. Chanock, Daniele Campa, Julie E. Buring, Bas Bueno-de-Mesquita, Amanda L. Blackford, Sonja I. Berndt, William R. Bamlet, Ana Babic, Gabriella Andreotti, Demetrius Albanes, Wei Zheng, Emily White, Kala Visvanathan, Xiao-Ou Shu, Rachel E. Neale, Loic Le Marchand, Charles Kooperberg, Phyllis J. Goodman, Graham G. Giles, Steven Gallinger, Mengmeng Du, Federico Canzian, Paul Brennan, Paige M. Bracci, Laura E. Beane-Freeman, Alan A. Arslan, William Wheeler, Prosenjit Kundu, and Evelina Mocci

Abstract

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.Significance:This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

Published
2023

15. Supplementary table 8 from Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Author

Rachael Stolzenberg-Solomon, Alison P. Klein, Nilanjan Chatterjee, Peter Kraft, Harvey A. Risch, Brian M. Wolpin, Gloria M. Petersen, Eric J. Jacobs, Donghui Li, Laufey T. Amundadottir, Anne Zeleniuch-Jacquotte, Fangcheng Yuan, Herbert Yu, Lynne R. Wilkens, Nicolas Wentzensen, Jean Wactawski-Wende, Stephen K. Van Den Eeden, Antonia Trichopoulou, Anne Tjonneland, Ian M. Thompson, Oliver Strobel, Victoria L. Stevens, Debra T. Silverman, Howard D. Sesso, Ghislaine Scelo, Nathaniel Rothman, Elio Riboli, Kari G. Rabe, Miquel Porta, Ulrike Peters, Salvatore Panico, Ann L. Oberg, Kimmie Ng, Roger L. Milne, Núria Malats, I-Min Lee, Robert C. Kurtz, Rayjean J. Hung, Robert N. Hoover, Elizabeth A. Holly, Manal M. Hassan, Patricia Hartge, Michael G. Goggins, Edward L. Giovannucci, J. Michael Gaziano, Charles S. Fuchs, Eric J. Duell, Erica J. Childs, Stephen J. Chanock, Daniele Campa, Julie E. Buring, Bas Bueno-de-Mesquita, Amanda L. Blackford, Sonja I. Berndt, William R. Bamlet, Ana Babic, Gabriella Andreotti, Demetrius Albanes, Wei Zheng, Emily White, Kala Visvanathan, Xiao-Ou Shu, Rachel E. Neale, Loic Le Marchand, Charles Kooperberg, Phyllis J. Goodman, Graham G. Giles, Steven Gallinger, Mengmeng Du, Federico Canzian, Paul Brennan, Paige M. Bracci, Laura E. Beane-Freeman, Alan A. Arslan, William Wheeler, Prosenjit Kundu, and Evelina Mocci

Abstract

Supplemental Table 8. Enrichment in regulatory regions for rs842357 and related SNPs

Published
2023

17. Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Author

Mengmeng Du, Rachael Z. Stolzenberg-Solomon, Herbert Yu, Paige M. Bracci, Antonia Trichopoulou, Anne Tjønneland, Eric J. Duell, Bas Bueno-de-Mesquita, Alison P. Klein, Graham G. Giles, Fangcheng Yuan, Howard D. Sesso, Federico Canzian, Sonja I. Berndt, I-Min Lee, Ghislaine Scelo, Lynne R. Wilkens, Jean Wactawski-Wende, Nicolas Wentzensen, Kari G. Rabe, Laufey T. Amundadottir, Eric J. Jacobs, Victoria L. Stevens, Phyllis J. Goodman, Harvey A. Risch, Edward Giovannucci, Evelina Mocci, Stephen K. Van Den Eeden, Stephen J. Chanock, Ann L. Oberg, Gloria M. Petersen, Rayjean J. Hung, Robert C. Kurtz, Xiao-Ou Shu, Charles Kooperberg, Charles S. Fuchs, Nilanjan Chatterjee, Nathaniel Rothman, Ulrike Peters, Núria Malats, Kimmie Ng, Ian M. Thompson, Roger L. Milne, William Wheeler, Paul Brennan, Emily White, J. Michael Gaziano, Steven Gallinger, Prosenjit Kundu, Wei Zheng, Miquel Porta, Brian M. Wolpin, Kala Visvanathan, Loic Le Marchand, Elio Riboli, Oliver Strobel, Michael Goggins, Daniele Campa, Salvatore Panico, Rachel E. Neale, Laura E. Beane Freeman, Gabriella Andreotti, Debra T. Silverman, Ana Babic, Erica J. Childs, Donghui Li, Julie E. Buring, Patricia Hartge, Manal M. Hassan, Alan A. Arslan, Robert N. Hoover, Amanda L. Blackford, Anne Zeleniuch-Jacquotte, Demetrius Albanes, William R. Bamlet, Peter Kraft, and Elizabeth A. Holly

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Pancreatic ductal adenocarcinoma, Genotype, Quantitative Trait Loci, Polymorphism, Single Nucleotide, Article, Chromosomes, Germline, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Pancreatic cancer, Internal medicine, medicine, Humans, SNP, Genetic Predisposition to Disease, Polymorphism, Genetic association, business.industry, Cyclin T, Carcinoma, Smoking, Membrane Proteins, Colocalization, Single Nucleotide, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Pancreatic Ductal, Chromosomes, Human, Pair 2, 030220 oncology & carcinogenesis, Pair 2, Expression quantitative trait loci, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study, business, Human
Abstract

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. Significance: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

Published
2021

18. Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk

Author

Núria Malats, Paul Brennan, Veronica Wendy Setiawan, Yaohua Yang, Jirong Long, Thilo Hackert, Xiaoliang Wang, Charles Kooperberg, Michael Goggins, Manal M. Hassan, I-Min Lee, Elizabeth A. Holly, Graham G. Giles, Roger L. Milne, Brian M. Wolpin, Miquel Porta, Verena Katske, Sonja I. Berndt, Herbert Yu, Laura E. Beane Freeman, Kari G. Rabe, Jean Wactawski-Wende, Robert N. Hoover, Stephen J. Chanock, Paige M. Bracci, Fei Ye, Ann L. Oberg, Wei Zheng, Anne Zeleniuch-Jacquotte, Lauren K. Brais, Samuel O. Antwi, Pilar Amiano, Nicolas Wentzensen, J. Michael Gaziano, Dalia Ghoneim, Jingjing Zhu, Rachel E. Neale, Charles S. Fuchs, Nathaniel Rothman, Ghislaine Scelo, Philip C Haycock, Alison P. Klein, Neil Murphy, Harvey A. Risch, Nikhil K. Khankari, Lynne R. Wilkens, Laufey T. Amundadottir, Peter Kraft, Mengmeng Du, Eric J. Jacobs, Federico Canzian, Ian M. Thompson, Alan A. Arslan, Howard D. Sesso, Emily White, Eric J. Duell, Gloria M. Petersen, Phyllis J. Goodman, Stolzenberg-Solomon R, Xiao-Ou Shu, Harvey J. Murff, Priya Duggal, Kathy J. Helzlsouer, Steven Gallinger, Demetrius Albanes, Bas Bueno-de-Mesquita, William R. Bamlet, Kai Yu, Gabriella Andreotti, Lang Wu, Peter T. Campbell, Robert C. Kurtz, Debra T. Silverman, Ana Babic, Julie E. Buring, Kala Visvanathan, and Loic Le Marchand

Subjects
Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Linoleic acid, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Fatty Acids, Omega-6, Internal medicine, Pancreatic cancer, Mendelian randomization, Humans, Medicine, Aged, chemistry.chemical_classification, business.industry, Mendelian Randomization Analysis, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Pancreatic Neoplasms, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Cohort, Female, business, Polyunsaturated fatty acid
Abstract

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case–Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98–1.02; arachidonic acid OR = 1.00, 95% CI = 0.99–1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87–1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

Published
2020

19. A blueprint for examining striatal control of cognition

Author

Elizabeth N. Holly, Edgar Díaz-Hernández, and Marc V. Fuccillo

Subjects
Neostriatum, Mice, Cognition, Behavior, Animal, Movement, General Neuroscience, Decision Making, Neural Pathways, Animals, Choice Behavior, Article, Corpus Striatum
Abstract

A classic view of the striatum holds that activity in direct and indirect pathways oppositely modulates motor output. Whether this involves direct control of movement, or reflects a cognitive process underlying movement, remains unresolved. Here we find that strong, opponent control of behavior by the two pathways of the dorsomedial striatum depends on the cognitive requirements of a task. Furthermore, a latent state model (a hidden Markov model with generalized linear model observations) reveals that-even within a single task-the contribution of the two pathways to behavior is state dependent. Specifically, the two pathways have large contributions in one of two states associated with a strategy of evidence accumulation, compared to a state associated with a strategy of repeating previous choices. Thus, both the demands imposed by a task, as well as the internal state of mice when performing a task, determine whether dorsomedial striatum pathways provide strong and opponent control of behavior.

Published
2022

20. Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk

Author

Brian M. Wolpin, Fangcheng Yuan, Lynne R. Wilkens, Núria Malats, Alan A. Arslan, Verena Katzke, Charles Kooperberg, Manal M. Hassan, Kimmie Ng, Robert N. Hoover, Naomi Walsh, Nicolas Wentzensen, Bas Bueno-de-Mesquita, Rachael Z. Stolzenberg-Solomon, Sonja I. Berndt, Holger Kirsten, Alison P. Klein, Patricia Hartge, Steven Gallinger, Demetrius Albanes, Wei Zheng, Stephen J. Chanock, Federico Canzian, Ann L. Oberg, Paige M. Bracci, I-Min Lee, Kala Visvanathan, Loic Le Marchand, Herbert Yu, Ian M. Thompson, Anne Zeleniuch-Jacquotte, Eric J. Duell, Han Zhang, Jonas Rosendahl, William R. Bamlet, Paul Brennan, Rayjean J. Hung, Kari G. Rabe, Thilo Hackert, Lei Song, Xiaoliang Wang, Elizabeth A. Holly, Howard D. Sesso, Jean Wactawski-Wende, Rachel E. Neale, Laura E. Beane Freeman, Phyllis J. Goodman, Harvey A. Risch, Jianxin Shi, Charles S. Fuchs, Nathaniel Rothman, Gabriella Andreotti, Roger L. Milne, Robert C. Kurtz, Neil Murphy, Francisco X. Real, Miquel Porta, J. Michael Gaziano, William Wheeler, Pilar Amiano, Emily White, Debra T. Silverman, Ana Babic, Kai Yu, Ghislaine Scelo, Laufey T. Amundadottir, Mengmeng Du, Gloria M. Petersen, Peter T. Campbell, Xiao-Ou Shu, Graham G. Giles, Michael Goggins, Elizabeth A. Platz, Donghui Li, and Julie E. Buring

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Cholangitis, Sclerosing, Genome-wide association study, Disease, Inflammatory bowel disease, Gastroenterology, Article, Primary sclerosing cholangitis, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Pancreatitis, Chronic, Internal medicine, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Colitis, business.industry, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, digestive system diseases, Pancreatic Neoplasms, Celiac Disease, 030104 developmental biology, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Chronic Disease, Pancreatitis, Colitis, Ulcerative, business, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study
Abstract

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10−6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. Significance: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.

Published
2020

21. Genome-Wide Gene–Diabetes and Gene–Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia

Author

Sonja I. Berndt, Elizabeth A. Holly, Anne Zeleniuch-Jacquotte, Gloria M. Petersen, Herbert Yu, Xiao-Ou Shu, Steven Gallinger, Eric J. Jacobs, Eric J. Duell, Anne Tjønneland, Federico Canzian, Howard D. Sesso, William R. Bamlet, Rachel E. Neale, Peter Kraft, Jean Wactawski-Wende, J. Michael Gaziano, Harvey A. Risch, Gabriella Andreotti, Graham G. Giles, Robert C. Kurtz, Kari G. Rabe, Bas Bueno-de-Mesquita, Erica J. Childs, Ghislaine Scelo, Patricia Hartge, Robert N. Hoover, Phyllis J. Goodman, Amanda L. Blackford, Laufey T. Amundadottir, Hong Wei Tang, Alan A. Arslan, Mengmeng Du, Demetrius Albanes, Lai Jiang, Michael Goggins, Rachael Z. Stolzenberg-Solomon, Paige M. Bracci, Antonia Trichopoulou, Charles S. Fuchs, Nathaniel Rothman, I. Min Lee, Ian M. Thompson, Rayjean J. Hung, Nilanjan Chatterjee, Paul Brennan, Peng Wei, Emily White, Laura E. Beane Freeman, Roger L. Milne, Miquel Porta, Wei Zheng, Daniele Campa, Lynne R. Wilkens, Donghui Li, Stephen J. Chanock, Ann L. Oberg, Julie E. Buring, Ulrike Peters, Irene Orlow, Debra T. Silverman, Ana Babic, Nicolas Wentzensen, Brian M. Wolpin, Kala Visvanathan, Loic Le Marchand, Núria Malats, Manal H. Hassam, Charles Kooperberg, Kimmie Ng, and Alison P. Klein

Subjects
Male, 0301 basic medicine, Epidemiology, Population, Genome-wide association study, Single-nucleotide polymorphism, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Pancreatic cancer, Diabetes Mellitus, medicine, Humans, SNP, Obesity, education, Genetics, education.field_of_study, medicine.disease, Minor allele frequency, 030104 developmental biology, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Female, Body mass index, Genome-Wide Association Study
Abstract

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10−6) was observed in the meta-analysis (PGxE = 1.2 ×10−6, PJoint = 4.2 ×10−7). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

Published
2020

22. B-Cell NHL Subtype Risk Associated with Autoimmune Conditions and PRS

Author

Sophia S. Wang, Claire M. Vajdic, Martha S. Linet, Susan L. Slager, Jenna Voutsinas, Alexandra Nieters, Delphine Casabonne, James R. Cerhan, Wendy Cozen, Graciela Alarcón, Otoniel Martínez-Maza, Elizabeth E. Brown, Paige M. Bracci, Jennifer Turner, Henrik Hjalgrim, Parveen Bhatti, Yawei Zhang, Brenda M. Birmann, Christopher R. Flowers, Ora Paltiel, Elizabeth A. Holly, Eleanor Kane, Dennis D. Weisenburger, Marc Maynadié, Pierluigi Cocco, Lenka Foretova, Elizabeth Crabb Breen, Qing Lan, Angela Brooks-Wilson, Anneclaire J. De Roos, Martyn T. Smith, Eve Roman, Paolo Boffetta, Anne Kricker, Tongzhang Zheng, Christine F. Skibola, Jacqueline Clavel, Alain Monnereau, Stephen J. Chanock, Nathaniel Rothman, Yolanda Benavente, Patricia Hartge, Karin E. Smedby, Beckman Research Institute of the City of Hope, University of New South Wales [Sydney] (UNSW), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Mayo Clinic [Rochester], Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Epidemiología y Salud Pública (CIBERESP), University of California [Irvine] (UCI), University of California, University of Alabama at Birmingham [ Birmingham] (UAB), University of California [Los Angeles] (UCLA), University of California [San Francisco] (UCSF), Macquarie University [Sydney], Statens Serum Institut [Copenhagen], British Columbia Cancer Research Centre [British Columbia, Canada], Chinese Academy of Medical Sciences [Beijing, China] (CAMS), Peking Union Medical College [Beijing, China], Harvard Medical School [Boston] (HMS), Emory University [Atlanta, GA], Hadassah Hebrew University Medical Center [Jerusalem], University of York [York, UK], City of Hope Comprehensive Cancer Center [Duarte], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University of Cagliari, Masaryk Memorial Cancer Institute (RECAMO), Simon Fraser University (SFU.ca), Drexel University, University of California [Berkeley], Stony Brook University [SUNY] (SBU), State University of New York (SUNY), University of Bologna, The University of Sydney, Brown University, Centre for Research in Earth and Space Science [Toronto] (CRESS), York University [Toronto], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer environnement (EPICENE ), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER, Karolinska Institutet [Stockholm], European Commission, European Regional Development Fund, and National Cancer Institute

Subjects
B-Lymphocytes, Malalties autoimmunitàries, Epidemiology, Autoimmune diseases, Genomics, Article, Autoimmune Diseases, Genòmica, Oncology, immune system diseases, hemic and lymphatic diseases, Case-Control Studies, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Follicular, Genome-Wide Association Study
Abstract

Background: A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non–Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes. Methods: In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell–mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression. Results: We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08–1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59–2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell–mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction. Conclusions: Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions. Impact: Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL.

Published
2021

23. Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer

Author

Paula L. Hyland, Sonja I. Berndt, Michelle Cotterchio, Rayjean J. Hung, Stephen K. Van Den Eeden, Núria Malats, Sara H. Olson, Rachel E. Neale, Eric A. Klein, Gloria M. Petersen, Eric J. Duell, Ann L. Oberg, Naomi Walsh, Robert C. Kurtz, Kari G Chaffee, Anne Zeleniuch-Jacquotte, Elisabete Weiderpass, Elizabeth A Holly, Brian M. Wolpin, Vladimir Janout, Lauren K. Brais, Paul Brennan, Qi Yang, Federico Canzian, Patricia Hartge, Han Zhang, Irene Collins, Peter Kraft, S. Chanock, Satu Männistö, PanScan, Christopher A. Haiman, Erica J. Childs, Wei Zheng, Robert N. Hoover, Malin Sund, Ayelet Borgida, Joseph M. Herman, Rachael Z. Stolzenberg-Solomon, Harvey A. Risch, Gabriella Andreotti, Oliver Strobel, Julie E. Buring, Kala Visvanathan, Ivana Holcatova, Nicholas J. Wareham, Paige M. Bracci, Nathaniel Rothman, Zhaoming Wang, Alison P Klein, Howard D. Sesso, Graham G. Giles, Gary E. Goodman, Edward Giovannucci, Michael Goggins, Emily White, Demetrius Albanes, Phyllis J. Goodman, Sean Cleary, Roger L. Milne, Francisco X. Real, Kathy J. Helzlsouer, Miquel Porta, Charles S. Fuchs, B. Bueno-de-Mesquita, Thilo Hackert, Lingeng Lu, Ghislaine Scelo, Marie-Christine Boutron-Ruault, Ana Babic, Herbert Yu, Laura Beane-Freeman, PanC consortia, J. Michael Gaziano, Laufey T. Amundadottir, Mark D Thornquist, I-Min Lee, Ulrike Peters, Mingfeng Zhang, Donghui Li, Eric J. Jacobs, Evelina Mocci, William Wheeler, Kai Yu, William R. Bamlet, Gianluca Severi, Xiao O. Shu, Alpa V. Patel, Alan A. Arslan, Charles Kooperberg, D. Silverman, Daniel Laheru, Irene Orlow, Steven Gallinger, J. Wactawski-Wende, Geoffrey S Tobias, Loic LeMarchand, Nicolas Wentzensen, Lenka Foretová, Manal Hasan, and Department of Medical and Clinical Genetics

Subjects
EXPRESSION, Developmental genetics, Cancer Research, GENES, SUSCEPTIBILITY LOCI, Pàncrees -- Genètica, 3122 Cancers, Genome-wide association study, Single-nucleotide polymorphism, Computational biology, VARIANTS, Biology, Polymorphism, Single Nucleotide, Genome, 03 medical and health sciences, Pàncrees -- Malalties, 0302 clinical medicine, Pancreatic cancer, ENDOTHELIN, medicine, Humans, BREAST-CANCER, Genetic Predisposition to Disease, TRANSCRIPTOME, Gene, Càncer de pàncrees, Pancreas cancer, Pàncrees -- Càncer, Genetic association, Models, Statistical, RECEPTOR, MUTATIONS, Case-control study, Articles, medicine.disease, 3. Good health, Pancreatic Neoplasms, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Meta-analysis, METASTASIS, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study, Genètica del desenvolupament
Abstract

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P

Published
2018

24. Striatal low-threshold spiking interneurons locally gate dopamine during learning

Author

Elizabeth N. Holly, Marc V. Fuccillo, Rodrigo A. España, and M. Felicia Davatolhagh

Subjects
Striatal dopamine, nervous system, In vivo, Dopamine, Chemistry, Dorsomedial striatum, Fast-scan cyclic voltammetry, medicine, Operant conditioning, Gating, Neuroscience, medicine.drug
Abstract

Low-threshold spiking interneurons (LTSIs) in the dorsomedial striatum are potent modulators of goal-directed learning. Here, we uncover a novel function for LTSIs in locally and directly gating striatal dopamine, using in vitro fast scan cyclic voltammetry as well as in vivo GRAB-DA sensor imaging and pharmacology during operant learning. We demonstrate that LTSIs, acting via GABAB signaling, attenuate dopamine release, thereby serving as local coordinators of striatal plasticity.

Published
2020

25. A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer

Author

William R. Bamlet, Alpa V. Patel, Mingfeng Zhang, Eric J. Jacobs, Tongwu Zhang, Evelina Mocci, Demetrius Albanes, Nilanjan Chatterjee, Alan A. Arslan, Phyllis J. Goodman, Wenming Xiao, Irene Collins, Ghislaine Scelo, Howard D. Sesso, Manolis Kogevinas, Lang Wu, Patricia Hartge, Manal Hasan, Jill P. Smith, Herbert Yu, Laufey T. Amundadottir, Geoffrey S. Tobias, Nathaniel Rothman, Jean Wactawski-Wende, Mengmeng Du, Edward Giovannucci, Stephen K. Van Den Eeden, Roger L. Milne, Irene Orlow, Elizabeth A. Holly, Kathy J. Helzlsouer, Miquel Porta, Ulrike Peters, Harvey A. Risch, Eric J. Duell, Steven Gallinger, Paige M. Bracci, Charles Kooperberg, Michael Goggins, Federico Canzian, Antonia Trichopoulou, Lei Song, Robert J. Kurtz, Brian M. Wolpin, Anne Zeleniuch-Jacquotte, Stephen J. Chanock, Gianluca Severi, Christopher A. Haiman, Loic LeMarchand, Ann L. Oberg, Jason W. Hoskins, Alison P. Klein, Kala Visvanathan, Gary E. Goodman, Gabriella Andreotti, Donghui Li, Charles C. Chung, Michelle Cotterchio, Lauren K. Brais, Satu Männistö, Núria Malats, Jianxin Shi, Charles S. Fuchs, Wei Zheng, Peter Kraft, Robert N. Hoover, J. Michael Gaziano, Erica J. Childs, Nicolas Wentzensen, Kai Yu, Paul Brennan, Mark D. Thornquist, Julie E. Buring, Anne Tjønneland, Jun Zhong, Kevin M. Brown, Ofure Obazee, Rachael Z. Stolzenberg-Solomon, Sabina Sieri, Bas Bueno-de-Mesquita, Debra T. Silverman, Ana Babic, Sonja I. Berndt, Chen Yuan, Ayelet Borgida, Rachel E. Neale, Eric A. Klein, Gloria M. Petersen, Xiao-Ou Shu, Kimmie Ng, Ashley Jermusyk, Graham G. Giles, Laura Beane-Freeman, Emily White, Malin Sund, Centre international de Recherche sur le Cancer (CIRC), Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay

Subjects
2. Zero hunger, Genetics, 0303 health sciences, Cancer Research, Candidate gene, [SDV]Life Sciences [q-bio], Genome-wide association study, Quantitative trait locus, Biology, medicine.disease, 3. Good health, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Pancreatic cancer, Genotype, medicine, PDX1, Pancreas, 030304 developmental biology
Abstract

Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Published
2020

26. HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author

Roel Vermeulen, Paulo Bofetta, Nicole Wong Doo, Mark P. Purdue, Eleanor Kane, Gilles Salles, Bengt Glimelius, Christine F. Skibola, Tongzhang Zheng, Graham G. Giles, Scott Davis, Pierluigi Cocco, Karin E. Smedby, Melissa C. Southey, Alexandra Nieters, Elizabeth A. Holly, Corrado Magnani, Paul Brennan, Stephanie J. Lax, David G. Cox, Lindsay M. Morton, Nikolaus Becker, Qing Lan, Elio Riboli, Herve Ghesquieres, Rudolph Kaaks, Jennifer Turner, Martha S. Linet, Anne Kricker, Stephanie J. Weinstein, Christopher R. Flowers, Alain Monnereau, Silvia de Sanjosé, Mary Carrington, John J. Spinelli, Patricia Hartge, Nathaniel Rothman, Yolanda Benavente, Susan L. Slager, Martha Glenn, Richard K. Severson, Ora Paltiel, Yawei Zhang, Ruth C. Travis, Demetrius Albanes, Nicola J. Camp, Paige M. Bracci, Jacqueline Clavel, James R. Cerhan, Marc Maynadié, Maria Grazia Ennas, Marie Hélène Delfau-Larue, Peter Kraft, Henrik Hjalgrim, Roger L. Milne, Alan A. Arslan, Jacob Musinsky, Martyn T. Smith, Anthony Staines, Lauren R. Teras, Jenna M. Voutsinas, Lenka Foretova, Sophia S. Wang, Hans-Olov Adami, Andrew L. Feldman, Wendy Cozen, Angela Brooks-Wilson, Kenneth Offit, Brian K. Link, Brenda M. Birmann, Sonja I. Berndt, Stephen J. Chanock, James McKay, Dennis D. Weisenburger, Claire M. Vajdic, Giancarlo Latte, Karen Curtin, W. Ryan Diver, Mads Melbye, Lucia Conde, Elizabeth E. Brown, Joseph Vijai, Eve Roman, Wang, Sophia S., Carrington, Mary, Berndt, Sonja I., Slager, Susan L., Bracci, Paige M., Voutsinas, Jenna, Cerhan, James R., Smedby, Karin E., Hjalgrim, Henrik, Vijai, Joseph, Morton, Lindsay M., Vermeulen, Roel, Paltiel, Ora, Vajdic, Claire M., Linet, Martha S., Nieters, Alexandra, de Sanjose, Silvia, Cozen, Wendy, Brown, Elizabeth E., Turner, Jennifer, Spinelli, John J., Zheng, Tongzhang, Birmann, Brenda M., Flowers, Christopher R., Becker, Nikolau, Holly, Elizabeth A., Kane, Eleanor, Weisenburger, Denni, Maynadie, Marc, Cocco, Pierluigi, Albanes, Demetriu, Weinstein, Stephanie J., Teras, Lauren R., Diver, W. Ryan, Lax, Stephanie J., Travis, Ruth C., Kaaks, Rudolph, Riboli, Elio, Benavente, Yolanda, Brennan, Paul, McKay, Jame, Delfau-Larue, Marie-Hélène, Link, Brian K., Magnani, Corrado, Ennas, Maria Grazia, Latte, Giancarlo, Feldman, Andrew L., Doo, Nicole Wong, Giles, Graham G., Southey, Melissa C., Milne, Roger L., Offit, Kenneth, Musinsky, Jacob, Arslan, Alan A., Purdue, Mark P., Adami, Hans-Olov, Melbye, Mad, Glimelius, Bengt, Conde, Lucia, Camp, Nicola J., Glenn, Martha, Curtin, Karen, Clavel, Jacqueline, Monnereau, Alain, Cox, David G., Ghesquières, Hervé, Salles, Gille, Boffetta, Paolo, Foretova, Lenka, Staines, Anthony, Davis, Scott, Severson, Richard K., Lan, Qing, Brooks-Wilson, Angela, Smith, Martyn T., Roman, Eve, Kricker, Anne, Zhang, Yawei, Kraft, Peter, Chanock, Stephen J., Rothman, Nathaniel, Hartge, Patricia, and Skibola, Christine F.

Subjects
Male, 0301 basic medicine, Heterozygote, Cancer Research, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Chronic lymphocytic leukemia, EPIDEMIOLOGIC RESEARCH, Genome-wide association study, Human leukocyte antigen, Biology, CLASSIFICATION, ANTIGENS, Article, Genetic Heterogeneity, 03 medical and health sciences, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, INTERLYMPH, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Prospective Studies, GENOME-WIDE ASSOCIATION, Allele, HLA Complex, Science & Technology, Hematology, CHRONIC LYMPHOCYTIC-LEUKEMIA, Genetic heterogeneity, Lymphoma, Non-Hodgkin, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, HETEROZYGOTE ADVANTAGE, medicine.disease, 3. Good health, Lymphoma, 030104 developmental biology, Oncology, Case-Control Studies, Immunology, B-VIRUS INFECTION, Female, Life Sciences & Biomedicine, NEOPLASMS, Genome-Wide Association Study
Abstract

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Published
2018

27. Integrated anatomical and physiological mapping of striatal afferent projections

Author

Elizabeth N. Holly, Marc V. Fuccillo, Kyuhyun Choi, Kevin T. Beier, and M. Felicia Davatolhagh

Subjects
Male, Interneuron, Thalamus, Mice, Transgenic, Striatum, Optogenetics, Biology, Medium spiny neuron, Gyrus Cinguli, Article, Synapse, Mice, 03 medical and health sciences, 0302 clinical medicine, Interneurons, Cortex (anatomy), medicine, Animals, Neurons, Afferent, 030304 developmental biology, 0303 health sciences, General Neuroscience, Mice, Inbred C57BL, Neostriatum, medicine.anatomical_structure, nervous system, Excitatory postsynaptic potential, Nerve Net, Neuroscience, 030217 neurology & neurosurgery
Abstract

The dorsomedial striatum, a key site of reward-sensitive motor output, receives extensive afferent input from cortex, thalamus and midbrain. These projections are integrated by striatal microcircuits containing both spiny projection neurons and local circuit interneurons. To explore target cell specificity of these projections, we compared inputs onto D1-dopamine receptor-positive spiny neurons, parvalbumin-positive fast-spiking interneurons and somatostatin-positive low-threshold-spiking interneurons, using cell type-specific rabies virus tracing and optogenetic-mediated projection neuron recruitment in mice. While the relative proportion of retrogradely labelled projection neurons was similar between target cell types, the convergence of inputs was systematically higher for projections onto fast-spiking interneurons. Rabies virus is frequently used to assess cell-specific anatomical connectivity but it is unclear how this correlates to synaptic connectivity and efficacy. To test this, we compared tracing data with target cell-specific measures of synaptic efficacy for anterior cingulate cortex and parafascicular thalamic projections using novel quantitative optogenetic measures. We found that target-specific patterns of convergence were extensively modified according to region of projection neuron origin and postsynaptic cell type. Furthermore, we observed significant divergence between cell type-specific anatomical connectivity and measures of excitatory synaptic strength, particularly for low-threshold-spiking interneurons. Taken together, this suggests a basic uniform connectivity map for striatal afferent inputs upon which presynaptic-postsynaptic interactions impose substantial diversity of physiological connectivity.

Published
2018

28. Striatal low-threshold spiking interneurons locally gate dopamine

Author

Marc V. Fuccillo, Elizabeth N. Holly, Rodrigo A. España, and M. Felicia Davatolhagh

Subjects
education.field_of_study, Interneuron, Dopamine, Dopaminergic, Population, Fast-scan cyclic voltammetry, Striatum, GABAB receptor, Biology, Article, Corpus Striatum, General Biochemistry, Genetics and Molecular Biology, medicine.anatomical_structure, Reward, nervous system, Interneurons, Synaptic plasticity, medicine, Learning, General Agricultural and Biological Sciences, education, Neuroscience, medicine.drug
Abstract

Summary The dorsomedial striatum (DMS) is a central hub supporting goal-directed learning and motor performance. Recent evidence has revealed unexpected roles for local inhibitory GABAergic networks in modulating striatal output and behavior.1 The sparse low-threshold spiking interneuron subtype (LTSI), which exhibits robust reward-circumscribed population activity, is a bidirectional regulator of initial goal-directed learning.2 Striatal dopamine signaling is a central reward-related neuromodulatory system mediating goal-directed action and performance, serving as a teaching signal,3 facilitating synaptic plasticity,4 and invigorating motor behaviors.5 Given the dynamic modulation of LTSIs during goal-directed behavior, we hypothesized that they could provide a novel GABAergic mechanism of local striatal dopaminergic regulation to shape early learning. We provide anatomical evidence for close proximation of LTSI terminals and dopaminergic processes in striatum, suggesting that LTSIs directly control dopaminergic axon activity. Using in vitro fast scan cyclic voltammetry, we demonstrate that LTSIs directly attenuate optogenetically evoked dopamine via GABAB receptor signaling. In vivo, GRABDA dopamine sensor imaging shows that LTSIs strongly modulate striatal dopamine dynamics during operant learning, while pharmacological stabilization of dopamine via intra-striatal aripiprazole microinjection suppresses the effects of LTSI inhibition on learning. Together, these results uncover an unexpected function for LTSIs in gating striatal dopamine to facilitate goal-directed learning.

Published
2021

29. Colposcopic characteristics and Lugol׳s staining differentiate anal high-grade and low-grade squamous intraepithelial lesions during high resolution anoscopy

Author

Joel M. Palefsky, Christine Miaskowski, Teresa M. Darragh, Elizabeth A. Holly, J. Michael Berry, Naomi Jay, and Misha Cohen

Subjects
medicine.medical_specialty, Pathology, HSIL, Lugol’s staining, Cervical Cancer, High resolution anoscopy, Gastroenterology, Article, lcsh:Infectious and parasitic diseases, Lesion, 03 medical and health sciences, 0302 clinical medicine, Vascularity, Clinical Research, Virology, Internal medicine, Atypia, medicine, Lugol's staining, lcsh:RC109-216, 030212 general & internal medicine, Cervix, Cancer, Colposcopy, medicine.diagnostic_test, business.industry, Lugol׳s staining, Anoscopy, medicine.disease, 3. Good health, Staining, Anal, Infectious Diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine.symptom, business
Abstract

Background: Anal squamous intraepithelial lesions (SIL) and cancers are increased in immunocompromised populations. Based upon anatomic and histologic similarities, the cervix is used as the model for anal screening. During cervical colposcopy, acetic acid (AA) and Lugol׳s staining (LS) result in characteristic changes that help distinguish low-grade (L)SIL from high-grade (H)SIL. Lesion characteristics were evaluated for their ability to distinguish anal (a)LSIL from anal (a)HSIL during high-resolution anoscopy after application of AA and LS. Methods: AA-stained lesions were described using standard cervical colposcopic criteria. LS was then applied and lesions were characterized as Lugol׳s-negative (L−), Lugol׳s-partial (L+/−), or Lugol׳s positive (L+) and then biopsied. Biopsies were characterized as benign, squamous atypia, LSIL or HSIL. Results: 835 anal lesions were analyzed. Sensitivity and positive predictive value (PPV) for aHSIL were highest for characteristics associated with cervical (c)HSIL. L− was independently associated with aHSIL (OR=4.7, 95% CI=3.4–6.7). In multiple logistic regression analysis, significant predictors of aHSIL were flat contour (OR=2.24, 95% CI=1.3–3.8), mosaic pattern (OR=2.0, 95% CI=1.4–2.9), vascular punctation (OR=1.5, 95% CI=1.1–2.1) and L− (OR=2.3, 95% CI=1.5–3.4). L− staining improved the PPV of aHSIL almost twofold in lesions that otherwise had a colposcopic impression of LSIL. Conclusions: Evaluating acetowhite lesions for contour, surface, vascularity, and LS may maximize the likelihood of identifying aHSIL. Keywords: Anal, HSIL, High resolution anoscopy, Lugol׳s staining

Published
2015
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30. Analysis of Heritability and Genetic Architecture of Pancreatic Cancer: A PanC4 Study

Author

Gloria M. Petersen, Donghui Li, Steven Gallinger, Michael Borges, Ghislaine Scelo, Evelina Mocci, Herbert Yu, Manal J. Hassan, Alison P. Klein, Kari G. Chaffee, Elizabeth A. Holly, Erica J. Childs, Irene Orlow, Paul Brennan, Ann L. Oberg, Paige M. Bracci, Fei Chen, Harvey A. Risch, Robert C. Kurtz, Sara H. Olson, Amanda L. Blackford, William R. Bamlet, Rachel E. Neale, Michael Goggins, Rayjean J. Hung, and Priya Duggal

Subjects
0301 basic medicine, Genetics, Male, Linkage disequilibrium, Epidemiology, Genome-wide association study, Disease, Heritability, Biology, Middle Aged, medicine.disease, Genetic architecture, Article, Minor allele frequency, Pancreatic Neoplasms, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Pancreatic cancer, medicine, Humans, Female, Gene
Abstract

Background: Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. Methods: Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. Results: Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. Conclusions: Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. Impact: Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.

Published
2018

31. Increased mesocorticolimbic dopamine during acute and repeated social defeat stress: modulation by corticotropin releasing factor receptors in the ventral tegmental area

Author

Klaus A. Miczek, Joseph F. DeBold, and Elizabeth N. Holly

Subjects
Male, endocrine system, Microdialysis, medicine.medical_specialty, Corticotropin-Releasing Hormone, Dopamine, Prefrontal Cortex, Neuropeptide, Nucleus accumbens, Receptors, Corticotropin-Releasing Hormone, Article, Nucleus Accumbens, Social defeat, Internal medicine, medicine, Animals, Rats, Long-Evans, Prefrontal cortex, Pharmacology, Chemistry, musculoskeletal, neural, and ocular physiology, Ventral Tegmental Area, Dopaminergic, Rats, Ventral tegmental area, Endocrinology, medicine.anatomical_structure, Social Dominance, nervous system, Neuroscience, Stress, Psychological, hormones, hormone substitutes, and hormone antagonists, psychological phenomena and processes, medicine.drug
Abstract

Stress activates a subset of dopamine neurons in the ventral tegmental area (VTA), increasing extracellular dopamine in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcSh). The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1 and CRF-R2) are located within the VTA and directly and indirectly influence dopaminergic activity. However, it has yet to be shown in vivo whether VTA CRF receptor activation is necessary for acute and repeated stress-induced dopamine efflux. With intra-VTA CRF-R1 and CRF-R2 antagonism during social defeat, we assessed whether blockade of these receptors could prevent stress-induced dopamine increases in the mPFC and NAcSh using in vivo microdialysis. Rats were microinjected with a CRF-R1 or CRF-R2 antagonist into the VTA prior to social defeat stress on days 1, 4, 7, and 10. In vivo microdialysis for dopamine in the mPFC and NAcSh was performed during stress on days 1 and 10. During the first social defeat, extracellular dopamine was significantly elevated in both the mPFC and NAcSh, and this increase in the NAcSh was blocked by intra-VTA CRF-R2, but not CRF-R1, antagonism. During the final social defeat, the dopaminergic increase was neither sensitized nor habituated in the mPFC and NAcSh, and intra-VTA CRF-R2, but not CRF-R1, antagonism prevented the dopamine increase in both brain regions. These findings show that CRF-R2 in the VTA is necessary for acute and repeated stress-induced dopamine efflux in the NAcSh, but is only recruited into mPFC-projecting dopamine neurons with repeated stress exposure.

Published
2015

32. Statin use and risk of pancreatic cancer: Results from a large, clinic-based case-control study

Author

Andrew H. Ko, Evan J. Walker, Elizabeth A. Holly, and Paige M. Bracci

Subjects
Cancer Research, Reduced risk, medicine.medical_specialty, biology, business.industry, Case-control study, Statin treatment, medicine.disease, Bioinformatics, Endocrinology, Oncology, Pancreatic cancer, Internal medicine, Hypolipidemic Agents, HMG-CoA reductase, medicine, biology.protein, lipids (amino acids, peptides, and proteins), Young adult, Cancer risk, business
Abstract

Background Statins are cholesterol-lowering medications with pleiotropic effects including alterations in growth signaling as well as immunomodulatory and anti-inflammatory effects that may alter cancer risk. Evidence from previous epidemiologic studies is inconsistent regarding whether statin use is associated with reduced risk of pancreatic cancer (PC).

Published
2015

33. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer

Author

Herbert Yu, Gabriele Capurso, Robert N. Hoover, Beatrice Mohelnikova-Duchonova, Amanda L. Blackford, Harvey A. Risch, H. Bas Bueno-de-Mesquita, Timothy J. Key, Stephen J. Chanock, Ann L. Oberg, Federico Canzian, Lingeng Lu, Maria Gazouli, Michelle Cotterchio, Daniele Campa, John P. Neoptolemos, Claudio Pasquali, Rachel E. Neale, Rayjean J. Hung, William R. Bamlet, Raffaele Pezzilli, Stefano Landi, Juozas Kupcinskas, Joseph M. Herman, Erica J. Childs, Ivana Holcatova, Steven Gallinger, Manal M. Hassan, Ewa Małecka-Panas, Pavel Vodicka, Donghui Li, Maarten F. Bijlsma, Irene Orlow, Lenka Foretova, Robert C. Kurtz, Yogesh K. Vashist, Francesca Tavano, Evelina Mocci, Amethyst Saldia, Michael Borges, Sean P. Cleary, Gloria M. Petersen, Brian M. Wolpin, Sara H. Olson, Kari G. Chaffee, Aldo Scarpa, Vladimir Janout, Elizabeth A. Holly, Niccola Funel, Hermann Brenner, Ghislaine Scelo, Laufey T. Amundadottir, Rachael Z. Stolzenberg-Solomon, Paige M. Bracci, Charles S. Fuchs, Paul Brennan, Oliver Strobel, Michael Goggins, Giulia Martina Cavestro, Cosmeri Rizzato, Andrea Mambrini, Alison P. Klein, CCA -Cancer Center Amsterdam, Radiotherapy, Childs, Ej, Mocci, E, Campa, D, Bracci, Pm, Gallinger, S, Goggins, M, Li, D, Neale, Re, Olson, Sh, Scelo, G, Amundadottir, Lt, Bamlet, Wr, Bijlsma, Mf, Blackford, A, Borges, M, Brennan, P, Brenner, H, Bueno de Mesquita, Hb, Canzian, F, Capurso, G, Cavestro, GIULIA MARTINA, Chaffee, Kg, Chanock, Sj, Cleary, Sp, Cotterchio, M, Foretova, L, Fuchs, C, Funel, N, Gazouli, M, Hassan, M, Herman, Jm, Holcatova, I, Holly, Ea, Hoover, Rn, Hung, Rj, Janout, V, Key, Tj, Kupcinskas, J, Kurtz, Rc, Landi, S, Lu, L, Malecka Panas, E, Mambrini, A, Mohelnikova Duchonova, B, Neoptolemos, Jp, Oberg, Al, Orlow, I, Pasquali, C, Pezzilli, R, Rizzato, C, Saldia, A, Scarpa, A, Stolzenberg Solomon, Rz, Strobel, O, Tavano, F, Vashist, Yk, Vodicka, P, Wolpin, Bm, Yu, H, Petersen, Gm, Risch, Ha, and Klein, A. P.

Subjects
Male, pancreatic cancer, Genome-wide association study, Gastroenterology, Aged, Australia, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 7, Europe, Female, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Middle Aged, North America, Pancreatic Neoplasms, Risk Factors, Polymorphism, Single Nucleotide, Genetics, Medicine (all), 0302 clinical medicine, CDKN2A, 0303 health sciences, Single Nucleotide, 3. Good health, 030220 oncology & carcinogenesis, Pair 3, Pair 2, Pair 7, Human, medicine.medical_specialty, PALB2, Biology, Article, Chromosomes, 03 medical and health sciences, Internal medicine, ABO blood group system, Pancreatic cancer, medicine, Polymorphism, 030304 developmental biology, Pair 17, Odds ratio, medicine.disease, Confidence interval, pancreatic cancer, genome-wide association study
Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

Published
2015

34. Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma

Author

Mariagrazia Zucca, Thomas M. Habermann, Lauren R. Teras, Joseph Vijai, Lenka Foretova, Simon Crouch, Anneclaire J. De Roos, Jacqueline Clavel, Lindsay M. Morton, Melissa C. Southey, W. Ryan Diver, Patrick M. Gaffney, James McKay, Eve Roman, Sophia S. Wang, Mark P. Purdue, Hans-Olov Adami, Gilles Salles, Jarmo Virtamo, Yan W. Asmann, Angela Brooks-Wilson, Thierry Jo Molina, Andrew D. Zelenetz, Ahmet Dogan, Kenneth Offit, Peter Kraft, Gianluca Severi, Zhaoming Wang, Tongzhang Zheng, Sonja I. Berndt, Brian K. Link, Sasha Bernatsky, Theodore R. Holford, Emanuele Angelucci, Paige M. Bracci, Martyn T. Smith, Stephen J. Chanock, Brenda M. Birmann, Hervé Ghesquières, Stephen M. Ansell, Paolo Vineis, Mads Melbye, Kari E. North, Jenny Turner, Jacques Riby, Charles E. Lawrence, Alain Monnereau, Nikolaus Becker, Lucia Conde, James R. Cerhan, Susan L. Slager, Demetrius Albanes, Henrik Hjalgrim, Hervé Tilly, Héctor A. Velásquez García, Rebecca D. Jackson, Ann E. Clarke, Elizabeth A. Holly, Robert J. Klein, Paolo Boffetta, Mark Liebow, Karin E. Smedby, Marco Rais, David G. Cox, Patricia Hartge, Rosalind Ramsey-Goldman, Rachel S. Kelly, Lesley F. Tinker, Christine F. Skibola, Wendy Cozen, Tracy Lightfoot, Anne J. Novak, Heiner Boeing, Roel Vermeulen, Claire M. Vajdic, Bengt Glimelius, Kimberly A. Bertrand, Marc Maynadie, Eleanor Kane, Nathaniel Rothman, Yolanda Benavente, Paul Brennan, Anne Tjønneland, John J. Spinelli, Qing Lan, Anne Kricker, Alex Smith, Anthony Staines, Graham G. Giles, Carrie A. Thompson, Thomas E. Witzig, Stephanie J. Weinstein, Karen H. Cotenbader, Corinne Haioun, Anne Zeleniuch-Jacquotte, Simonetta Di Lollo, Alexandra Nieters, Rudolph Kaaks, Silvia de Sanjosé, Richard K. Severson, Yawei Zhang, Research Institute of the McGill University Health Centre, 1650 Cedar Avenue, Oklahoma Medical Research Foundation, Registre des hémopathies malignes de Côte d'Or, Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Bourgogne Franche-Comté ( UBFC ), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), University of Calgary, Bernatsky, S. and García, H.A.V. and Spinelli, J.J. and Gaffney, P. and Smedby, K.E. and Ramsey-Goldman, R. and Wang, S.S. and Adami, H.-O. and Albanes, D. and Angelucci, E. and Ansell, S.M. and WAsmann, Y. and Becker, N. and Benavente, Y. and Berndt, S.I. and Bertrand, K.A. and Birmann, B.M. and Boeing, H. and Boffetta, P. and Bracci, P.M. and Brennan, P. and Brooks-Wilson, A.R. and Cerhan, J.R. and Chanock, S.J. and Clavel, J. and Conde, L. and Cotenbader, K.H. and Cox, D.G. and Cozen, W. and Crouch, S. and De Roos, A.J. and De Sanjose, S. and Di Lollo, S. and Diver, W.R. and Dogan, A. and Foretova, L. and Ghesquières, H. and Giles, G.G. and Glimelius, B. and Habermann, T.M. and Haioun, C. and Hartge, P. and Hjalgrim, H. and Holford, T.R. and Holly, E.A. and Jackson, R.D. and Kaaks, R. and Kane, E. and Kelly, R.S. and Klein, R.J. and Kraft, P. and Kricker, A. and Lan, Q. and Lawrence, C. and Liebow, M. and Lightfoot, T. and Link, B.K. and Maynadie, M. and McKay, J. and Melbye, M. and Molina, T.J. and Monnereau, A. and Morton, L.M. and Nieters, A. and North, K.E. and Novak, A.J. and Offit, K. and Purdue, M.P. and Rais, M. and Riby, J. and Roman, E. and Rothman, N. and Salles, G. and Severi, G. and Severson, R.K. and Skibola, C.F. and Slager, S.L. and Smith, A. and Smith, M.T. and Southey, M.C. and Staines, A. and Teras, L.R. and Thompson, C.A. and Tilly, H. and Tinker, L.F. and Tjonneland, A. and Turner, J. and Vajdic, C.M. and Vermeulen, R.C.H. and Vijai, J. and Vineis, P. and Virtamo, J. and Wang, Z. and Weinstein, S. and Witzig, T.E. and Zelenetz, A. and Zeleniuch-Jacquotte, A. and Zhang, Y. and Zheng, T. and Zucca, M. and Clarke, A.E., McGill University Health Center [Montreal] (MUHC), Oklahoma Medical Research Foundation (OMRF), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, and dIRAS RA-I&I RA

Subjects
Oncology, medicine.medical_specialty, Immunology, Single-nucleotide polymorphism, Genome-wide association study, [SDV.CAN]Life Sciences [q-bio]/Cancer, lymphoma, Human leukocyte antigen, Bioinformatics, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Internal medicine, medicine, SNP, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, General Medicine, medicine.disease, Systemic lupus, Lupus Nephritis, Risk of diffuse large B-cell lymphoma, 3. Good health, Lymphoma, 030220 oncology & carcinogenesis, business, Diffuse large B-cell lymphoma, IRF5, malignancy
Abstract

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genomewide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE. © 2017 BMJ Publishing Group. All rights reserved.

Published
2017

35. Individual differences in anhedonic and accumbal dopamine responses to chronic social stress and their link to cocaine self-administration in female rats

Author

Klaus A. Miczek, Akiko Shimamoto, Joseph F. DeBold, Christopher O. Boyson, and Elizabeth N. Holly

Subjects
Male, medicine.medical_specialty, Dopamine, Microdialysis, Individuality, Self Administration, Nucleus accumbens, Nucleus Accumbens, Article, Social defeat, Cocaine-Related Disorders, Random Allocation, chemistry.chemical_compound, Saccharin, Sex Factors, Cocaine, Internal medicine, medicine, Animals, Rats, Long-Evans, Chronic stress, Social Behavior, Psychiatry, Pharmacology, Social stress, Depressive Disorder, Major, medicine.disease, Rats, Endocrinology, chemistry, Major depressive disorder, Female, Self-administration, Psychology, Stress, Psychological, medicine.drug
Abstract

Women are twice as likely as men to develop major depressive disorder. Exposure to chronic stress can induce depression in some vulnerable individuals, while others are resistant to depressive-like symptoms after equivalent levels of chronic stress. In female rats, individual differences in saccharin intake during chronic social defeat stress may predict subsequent cocaine self-administration, and may be attributed to alterations in mesolimbic dopamine activity. Female rats were exposed to 21 days of chronic social defeat stress, during which they were evaluated for their anhedonia-like responses in the form of saccharin intake. After chronic social defeat stress, the rats were tested for behavioral cross-sensitization to cocaine and escalated cocaine self-administration in a 24-h “binge.” A separate group of animals underwent in vivo microdialysis of the nucleus accumbens (NAc) shell to assess dopamine (DA) in response to acute cocaine challenge. Cluster analysis revealed two phenotypes among the stressed female rats based on their saccharin intake while being exposed to stress, termed stress-resistant (SR, 28 %) and stress-sensitive (SS, 72 %). The amount of cocaine self-administered during the 24-h “binge” was positively correlated with preceding saccharin intake. The NAc DA response to a cocaine challenge was significantly lower in SR rats than in the SS and non-stressed control rats. No other significant differences were observed in behavioral cross-sensitization or cocaine self-administration prior to the “binge.” Female rats showed individual differences in their anhedonic-like response to chronic social defeat stress, and these differences were reliably associated with subsequent cocaine-taking behavior.

Published
2014

36. Metformin use among type 2 diabetics and risk of pancreatic cancer in a clinic-based case-control study

Author

Andrew H. Ko, Evan J. Walker, Elizabeth A. Holly, and Paige M. Bracci

Subjects
Cancer Research, medicine.medical_specialty, business.industry, Case-control study, Type 2 diabetes, medicine.disease, Logistic regression, Metformin, Surgery, Oncology, Internal medicine, Diabetes mellitus, medicine, Population study, Observational study, Risk factor, business, medicine.drug
Abstract

A better understanding of the association between diabetes and pancreatic cancer (PC) may inform prevention and/or early detection strategies. Metformin has been associated with reduced risk of certain cancers, including PC, in some observational clinical studies. We assessed whether metformin use was associated with PC risk among those with type 2 diabetes (DM2), and whether metformin use modulated the association between DM2 and risk of PC. In total, 536 PC cases and 869 frequency-matched controls were recruited predominantly from University of California San Francisco medical clinics from 2006 to 2011. Eligible participants completed direct interviews using a structured risk factor questionnaire. The association between metformin use and PC risk was assessed using propensity score-weighted unconditional logistic regression methods in analyses restricted to diabetics and adjusted multivariable logistic models in the total study population. Ever use of metformin was not associated with PC risk in analyses restricted to DM2 (N = 170) participants (adjusted OR: 1.01, 95% CI: 0.61-1.68). In the total study population (N = 1,405) using nondiabetics as the referent group, PC risk was inversely associated with diabetes duration (ptrend

Published
2014

37. Medical History, Lifestyle, Family History, and Occupational Risk Factors for Marginal Zone Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

Author

Paige M, Bracci, Yolanda, Benavente, Jennifer J, Turner, Ora, Paltiel, Susan L, Slager, Claire M, Vajdic, Aaron D, Norman, James R, Cerhan, Brian C H, Chiu, Nikolaus, Becker, Pierluigi, Cocco, Ahmet, Dogan, Alexandra, Nieters, Elizabeth A, Holly, Eleanor V, Kane, Karin E, Smedby, Marc, Maynadié, John J, Spinelli, Eve, Roman, Bengt, Glimelius, Sophia S, Wang, Joshua N, Sampson, Lindsay M, Morton, and Silvia, de Sanjosé

Subjects
Adult, Aged, 80 and over, Male, Cancer Research, Australia, Comorbidity, Lymphoma, B-Cell, Marginal Zone, General Medicine, Middle Aged, Article, Europe, Young Adult, Oncology, Risk Factors, Case-Control Studies, Occupational Exposure, North America, Odds Ratio, Humans, Female, Life Style, Aged
Abstract

Marginal zone lymphoma (MZL), comprised of nodal, extranodal, and splenic subtypes, accounts for 5%-10% of non-Hodgkin lymphoma cases. A detailed evaluation of the independent effects of risk factors for MZL and its subtypes has not been conducted.Data were pooled from 1052 MZL cases (extranodal [EMZL] = 633, nodal [NMZL] = 157, splenic [SMZL] = 140) and 13766 controls from 12 case-control studies. Adjusted unconditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs).Novel findings for MZL subtypes include increased risk for B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14), hepatitis C virus seropositivity (EMZL OR = 5.29, 95% CI = 2.48 to 11.28), self-reported peptic ulcers (EMZL OR = 1.83, 95% CI = 1.35 to 2.49), asthma without other atopy (SMZL OR = 2.28, 95% CI = 1.23 to 4.23), family history of hematologic cancer (EMZL OR = 1.90, 95% CI = 1.37 to 2.62) and of non-Hodgkin lymphoma (NMZL OR = 2.82, 95% CI = 1.33 to 5.98), permanent hairdye use (SMZL OR = 6.59, 95% CI = 1.54 to 28.17), and occupation as a metalworker (NMZL OR = 3.56, 95% CI = 1.67 to 7.58). Reduced risks were observed with consumption of any alcohol (EMZL fourth quartile OR = 0.48, 95% CI = 0.28 to 0.82) and lower consumption of wine (NMZL first to third quartile ORs0.45) compared with nondrinkers, and occupation as a teacher (EMZL OR = 0.58, 95% CI = 0.37 to 0.88).Our results provide new data suggesting etiologic heterogeneity across MZL subtypes although a common risk of MZL associated with B-cell activating autoimmune conditions was found.

Published
2014

38. Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

Author

Paige M. Bracci, Thomas M. Habermann, Kenneth P. Cantor, Stefania Rodella, John J. Spinelli, Brenda M. Birmann, Paul Brennan, Alain Monnereau, Christina A. Clarke, Eva Negri, Susan L. Slager, Elizabeth A. Holly, Patricia Hartge, Silvia Franceschi, Sonja I. Berndt, Silvia de Sanjosé, Paolo Vineis, Qing Lan, Anneclaire J. De Roos, Paolo Crosignani, Jennifer Turner, Randy D. Gascoyne, Joanne S. Colt, Eve Roman, Richard K. Severson, Alexandra M. Levine, Emanuele Stagnaro, Bengt Glimelius, Marc Maynadié, Jonathan W. Friedberg, Yawei Zhang, Theodore R. Holford, Angela Brooks-Wilson, Oriana Nanni, Dennis D. Weisenburger, Joshua N. Sampson, Nathaniel Rothman, Yolanda Benavente, Andrew L. Feldman, Leslie Bernstein, Pierluigi Cocco, Marshall E. Kadin, Luigino Dal Maso, Valerio Ramazzotti, Lenka Foretova, Lucia Miligi, Sophia S. Wang, Rosario Tumino, Hans-Olov Adami, Wendy Cozen, Tracy Lightfoot, Sam M. Mbulaiteye, Jacqueline Clavel, Tongzhang Zheng, Paolo Boffetta, Anne Kricker, Martha S. Linet, Alexandra Nieters, Christine F. Skibola, Claire M. Vajdic, Nikolaus Becker, Laurent Orsi, Eleanor Kane, Diego Serraino, Carlo La Vecchia, Alex Smith, James M. Foran, Lindsay M. Morton, Anthony Staines, Simonetta Di Lollo, Mads Melbye, Jennifer L. Kelly, James R. Cerhan, Timothy G. Call, Henrik Hjalgrim, Christopher R. Flowers, Bruce K. Armstrong, Joseph M. Connors, Mark Liebow, Ora Paltiel, Ellen T. Chang, Aaron Blair, Karin E. Smedby, Carla Vindigni, Brian C.-H. Chiu, Adele Seniori Costantini, Scott Davis, Morton, L.M., Slager, S.L., Cerhan, J.R., Wang, S.S., Vajdic, C.M., Skibola, C.F., Bracci, P.M., de Sanjosé, S., Smedby, K.E., Chiu, B.C.H., Zhang, Y., Mbulaiteye, S.M., Monnereau, A., Turner, J.J., Clavel, J., Adami, H.-O., Chang, E.T., Glimelius, B., Hjalgrim, H., Melbye, M., Crosignani, P., di Lollo, S., Miligi, L., Nanni, O., Ramazzotti, V., Rodella, S., Costantini, A.S., Stagnaro, E., Tumino, R., Vindigni, C., Vineis, P., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Cocco, P., Foretova, L., Maynadié, M., Nieters, A., Staines, A., Colt, J.S., Cozen, W., Davis, S., de Roos, A.J., Hartge, P., Rothman, N., Severson, R.K., Holly, E.A., Call, T.G., Feldman, A.L., Habermann, T.M., Liebow, M., Blair, A., Cantor, K.P., Kane, E.V., Lightfoot, T., Roman, E., Smith, A., Brooks-Wilson, A., Connors, J.M., Gascoyne, R.D., Spinelli, J.J., Armstrong, B.K., Kricker, A., Holford, T.R., Lan, Q., Zheng, T., Orsi, L., Dal Maso, L., Franceschi, S., La Vecchia, C., Negri, E., Serraino, D., Bernstein, L., Levine, A., Friedberg, J.W., Kelly, J.L., Berndt, S.I., Birmann, B.M., Clarke, C.A., Flowers, C.R., Foran, J.M., Kadin, M.E., Paltiel, O., Weisenburger, D.D., Linet, M.S., and Sampson, J.N.

Subjects
Adult, Male, Cancer Research, Adolescent, Chronic lymphocytic leukemia, Follicular lymphoma, Comorbidity, Disease, Non-Hodgkin lymphoma (NHL), Article, Young Adult, Risk Factors, immune system diseases, Occupational Exposure, hemic and lymphatic diseases, Odds Ratio, medicine, Cluster Analysis, Humans, Risk factor, Family history, Life Style, Aged, Aged, 80 and over, International Lymphoma Epidemiology Consortium (InterLymph), business.industry, Lymphoma, Non-Hodgkin, Australia, Case-control study, General Medicine, Odds ratio, Middle Aged, medicine.disease, Lymphoma, Europe, Oncology, Case-Control Studies, North America, Immunology, Female, business
Abstract

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy and the fifth most common type of cancer in more developed regions of the world (1). Numerous NHL subtypes with distinct combinations of morphologic, immunophenotypic, genetic, and clinical features are currently recognized (2,3). The incidence of NHL subtypes varies substantially by age, sex, and race/ethnicity (4–7). However, the etiological implications of this biological, clinical, and epidemiological diversity are incompletely understood. The importance of investigating etiology by NHL subtype is clearly supported by research on immunosuppression, infections, and autoimmune diseases, which are the strongest and most established risk factors for NHL. Studies of solid organ transplant recipients and individuals infected with HIV demonstrate that risks are markedly increased for several—but not all—NHL subtypes (8–13). Some infections and autoimmune diseases are associated with a single specific subtype [eg, human T-cell lymphotropic virus, type I (HTLV-I) with adult T-cell leukemia/lymphoma (14), celiac disease with enteropathy-type peripheral T-cell lymphoma (PTCL) (15–17)], whereas others [eg, Epstein–Barr virus, hepatitis C virus (HCV), Sjogren’s syndrome (18–21)] have been associated with multiple subtypes. In the last two decades, reports from individual epidemiological studies of NHL have suggested differences in risks among NHL subtypes for a wide range of risk factors, but most studies have lacked the statistical power to assess any differences quantitatively and have not systematically evaluated combinations of subtypes. One study assessed multiple risk factors and found support for both etiologic commonality and heterogeneity for NHL subtypes, with risk factor patterns suggesting that immune dysfunction is of greater etiologic importance for diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma than for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (22). However, that analysis was limited to approximately 1300 NHL cases and considered only the four most common NHL subtypes. Pooling data from multiple studies through the International Lymphoma Epidemiology Consortium (InterLymph) have provided substantial insight into associations between specific risk factors and NHL subtypes, with evidence that family history of hematologic malignancy, autoimmune diseases, atopic conditions, lifestyle factors (smoking, alcohol, anthropometric measures, and hair dye use), and sun exposure are associated with NHL risk (19,21,23–32). However, no previous study has compared patterns of risk for a range of exposures for both common and rarer NHL subtypes. We undertook the InterLymph NHL Subtypes Project, a pooled analysis of 20 case–control studies including 17 471 NHL cases and 23 096 controls, to advance understanding of NHL etiology by investigating NHL subtype-specific risks associated with medical history, family history of hematologic malignancy, lifestyle factors, and occupation. The detailed risk factor profiles for each of 11 NHL subtypes appear in this issue (15–17,33–40). In this report, we assess risk factor heterogeneity among the NHL subtypes and identify subtypes that have similar risk factor profiles.

Published
2014

39. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Author

Hidemi Ito, Stephen K. Van Den Eeden, Abdisamad M. Ibrahim, Ching C. Lau, Preetha Rajaraman, Gloria M. Petersen, Judith Hoffman-Bolton, Colin P.N. Dinney, Chang Hyun Kang, Melinda C. Aldrich, Mark P. Purdue, Xiao-Ou Shu, William J. Blot, Sanjay Shete, Alpa V. Patel, Charles Kooperberg, Paolo Vineis, David Van Den Berg, Chao A. Hsiung, Anthony J. Swerdlow, Qing Lan, Wu Chou Su, Afshan Siddiq, Ulrike Peters, Katia Scotlandi, Sara H. Olson, Kendra Schwartz, Kelly L. Bolton, Chancellor Hohensee, Josep Lloreta, Kevin B. Jacobs, Debra T. Silverman, Rudolf Kaaks, Wei Zheng, Steven Gallinger, Junwen Wang, Angela Carta, Massimo Serra, Petra H.M. Peeters, Victoria L. Stevens, Yasushi Yatabe, Geraldine Cancel-Tassin, Joshua N. Sampson, Young Tae Kim, Graham A. Colditz, Pan-Chyr Yang, Baosen Zhou, Fredrick R. Schumacher, Nicolas Wentzensen, Evelyn Tay, Claudia Maria Hattinger, Chen Wu, Pilar Amiano, Mattias Johansson, Maxwell P. Lee, Christian P. Kratz, Michael B. Cook, Mingfeng Zhang, Kay-Tee Khaw, Jian-Min Yuan, Anne Zeleniuch-Jacquotte, Jinping Jia, Roberto Tirabosco, Jing Ma, Neil E. Caporaso, Christopher A. Haiman, Bu Tian Ji, Adrienne M. Flanagan, Neyssa Marina, Eric J. Jacobs, Sophia S. Wang, Chong-Jen Yu, Edward Giovannucci, Margaret Wrensch, Robert L. Grubb, Bin Zhu, Daniel O. Stram, Manolis Kogevinas, Margaret R. Karagas, Mazda Jenab, Alison M. Mondul, Jun Xu, Preethi S. Raj, Anders Ahlbom, Christine D. Berg, Shelley Niwa, Kala Visvanathan, Loic Le Marchand, Jorge R. Toro, Robert N. Hoover, Heather Spencer Feigelson, Michelle Brotzman, Laurence N. Kolonel, Krista A. Zanetti, Chengfeng Wang, Mary Ann Butler, Ann Truelove, Irene L. Andrulis, Hongbing Shen, H. Dean Hosgood, Ming Shyan Huang, Gee-Chen Chang, Jianjun Liu, John K. Wiencke, Stephanie J. Weinstein, Beatrice Melin, Kouya Shiraishi, Zhihua Yin, Lee E. Moore, Börje Ljungberg, Jolanta Lissowska, Elizabeth M. Gillanders, M. T. Landi, Cari M. Kitahara, Maria Feychting, Kuan-Yu Chen, Matthias Simon, Brian M. Wolpin, Hemang Parikh, Hannah P. Yang, Graham G. Giles, Alison Johnson, Demetrius Albanes, Carlos González, Brian E. Henderson, Xifeng Wu, Harvey A. Risch, Amy Hutchinson, Christopher Hautman, Constance Chen, Zhibin Hu, Donghui Li, Elio Riboli, Julie E. Buring, Curtis C. Harris, Xu Che, Núria Malats, Roger Henriksson, Rosario Tumino, Joanne S. Colt, Alfredo Carrato, Paolo Boffetta, Maria Pik Wong, Hideo Tanaka, Federico Canzian, Alan D. L. Sihoe, Chien-Jen Chen, Kenneth Muir, Chen Ying, Qincheng He, Melissa C. Southey, Marc Sanson, Victoria K. Cortessis, Sharon A. Savage, Wei Hu, Yao Tettey, Daniela S. Gerhard, Sofia Pavanello, Guangwen Cao, H. Barton Grossman, Michael Goggins, Hideo Kunitoh, Peter D. Inskip, Seth P. Lerner, Peter Kraft, David Thomas, Peng Guan, Chung Hsing Chen, I. Shou Chang, Christoffer Johansen, Roberta McKean-Cowdin, Lee J. Helman, Yuh Min Chen, Ana Patiño-García, Pär Stattin, Xiaoping Miao, Tangchun Wu, Jay S. Wunder, Ann W. Hsing, Yu-Tang Gao, Brooke L. Fridley, Tania Carreón, Charles C. Chung, Nan Hu, Yoo Jin Jung, Richard B. Biritwum, Eric J. Duell, Philip R. Taylor, Satu Männistö, Kai Yu, Meredith Yeager, Xia Pu, Vittorio Krogh, Anand P. Chokkalingam, Susan M. Gapstur, W. Ryan Diver, Yuanqing Ye, Keitaro Matsuo, Cecilia Arici, You-Lin Qiao, Alan R. Schned, Dominique S. Michaud, Joanne W. Elena, Christopher Kim, Dongxin Lin, Yun-Chul Hong, Daru Lu, Reina García-Closas, Jonine D. Figueroa, Linda M. Liao, Yi-Long Wu, Heiner Boeing, Mark Lathrop, Göran Hallmans, Elizabeth A. Holly, Carol Giffen, Andrew A. Adjei, Consol Serra, Anne Tjønneland, Joseph F. Fraumeni, Alisa M. Goldstein, Ruth C. Travis, Rebecca Troisi, Dalsu Baris, Nalan Gokgoz, Olivier Cussenot, Xiang Deng, Yeul Hong Kim, Malin Sund, Sonja I. Berndt, E. David Crawford, Edward D. Yeboah, Sook Whan Sung, Françoise Clavel-Chapelon, Woon-Puay Koh, Nilgun Kurucu, Richard B. Hayes, Ashish M. Kamat, Beata Peplonska, Laurie Burdette, Ze Zhang Tang, Alan A. Arslan, Malcolm C. Pike, Sabina Sierri, J. Michael Gaziano, Lorna H. McNeil, Katherine A. McGlynn, Ulla Vogel, Logan G. Spector, H. Bas Bueno-de-Mesquita, Stephen J. Chanock, Jae Yong Park, Jennifer Prescott, Fernando Lecanda, Margaret A. Tucker, Ti Ding, Christian C. Abnet, Jenny Chang-Claude, Dimitrios Trichopoulos, Wei-Yen Lim, Wen Tan, Nick Orr, Jin Hee Kim, Stefano Porru, Chand Khanna, Robert R. McWilliams, Zhaoming Wang, Jeong Seon Ryu, David V. Conti, Alison P. Klein, Adonina Tardón, Robert J. Klein, Rebecca J. Rodabough, Mark H. Greene, Aruna Kamineni, Jie Lin, Rachael Z. Stolzenberg-Solomon, Patricia Hartge, Susan E. Hankinson, Young-Chul Kim, In Sam Kim, Luis Sierrasesúmaga, Roel Vermeulen, Paige M. Bracci, Mariana C. Stern, Louise A. Brinton, Myron D. Gross, Yong-Bing Xiang, Chih Yi Chen, G. A. Gerald Andriole, Paul S. Meltzer, Ying-Huang Tsai, Faith G. Davis, Ulrika Andersson, Paul Brennan, Sara Lindström, Chaoyu Wang, Giuseppe Mastrangelo, Laufey T. Amundadottir, Immaculata De Vivo, Bryan A. Bassig, Elisabete Weiderpass, Takashi Kohno, Nilanjan Chatterjee, Margaret R. Spitz, Pier Alberto Bertazzi, William Wheeler, David J. Hunter, Wei Tang, Qiuyin Cai, Naomi E. Allen, Molly Schwenn, Emily White, Min Shen, Adeline Seow, Laura E. Beane Freeman, James E. Mensah, Howard D. Sesso, Anna Luisa Di Stefano, Amanda Black, Manuela Gago-Dominguez, Christine B. Ambrosone, Avima M. Ruder, Martha S. Linet, Meir J. Stampfer, Robert C. Kurtz, Donald A. Barkauskas, Lisa W. Chu, Montserrat Garcia-Closas, Jason W. Hoskins, Melissa A. Austin, Kyoung Mu Lee, Jianxin Shi, Charles S. Fuchs, Nathaniel Rothman, Richard Gorlick, Piero Picci, Gianluca Severi, Ann G. Schwartz, Jian Gu, Christopher I. Amos, Marie-Christine Boutron-Ruault, Salvatore Panico, Alicja Wolk, Sara S. Strom, Lisa Mirabello, Jin-Hu Fan, Chin-Fu Hsiao, Neal D. Freedman, Geoffrey S. Tobias, Julie M. Gastier-Foster, Wang, Z, Zhu, B, Zhang, M, Parikh, H, Jia, J, Chung, Cc, Sampson, Jn, Hoskins, Jw, Hutchinson, A, Burdette, L, Ibrahim, A, Hautman, C, Raj, P, Abnet, Cc, Adjei, Aa, Ahlbom, A, Albanes, D, Allen, Ne, Ambrosone, Cb, Aldrich, M, Amiano, P, Amos, C, Andersson, U, Andriole G., Jr, Andrulis, Il, Arici, C, Arslan, Aa, Austin, Ma, Baris, D, Barkauskas, Da, Bassig, Ba, Beane Freeman, Le, Berg, Cd, Berndt, Si, Bertazzi, Pa, Biritwum, Rb, Black, A, Blot, W, Boeing, H, Boffetta, P, Bolton, K, Boutron Ruault, Mc, Bracci, Pm, Brennan, P, Brinton, La, Brotzman, M, Bueno de Mesquita, Hb, Buring, Je, Butler, Ma, Cai, Q, Cancel Tassin, G, Canzian, F, Cao, G, Caporaso, Ne, Carrato, A, Carreon, T, Carta, A, Chang, Gc, Chang, I, Chang Claude, J, Che, X, Chen, Cj, Chen, Cy, Chen, Ch, Chen, C, Chen, Ky, Chen, Ym, Chokkalingam, Ap, Chu, Lw, Clavel Chapelon, F, Colditz, Ga, Colt, J, Conti, D, Cook, Mb, Cortessis, Vk, Crawford, Ed, Cussenot, O, Davis, Fg, De Vivo, I, Deng, X, Ding, T, Dinney, Cp, Di Stefano, Al, Diver, Wr, Duell, Ej, Elena, Jw, Fan, Jh, Feigelson, H, Feychting, M, Figueroa, Jd, Flanagan, Am, Fraumeni JF, Jr, Freedman, Nd, Fridley, Bl, Fuchs, C, Gago Dominguez, M, Gallinger, S, Gao, Yt, Gapstur, Sm, Garcia Closas, M, Garcia Closas, R, Gastier Foster, Jm, Gaziano, Jm, Gerhard, D, Giffen, Ca, Giles, Gg, Gillanders, Em, Giovannucci, El, Goggins, M, Gokgoz, N, Goldstein, Am, Gonzalez, C, Gorlick, R, Greene, Mh, Gross, M, Grossman, Hb, Grubb R., 3rd, Gu, J, Guan, P, Haiman, Ca, Hallmans, G, Hankinson, Se, Harris, Cc, Hartge, P, Hattinger, C, Hayes, Rb, He, Q, Helman, L, Henderson, Be, Henriksson, R, Hoffman Bolton, J, Hohensee, C, Holly, Ea, Hong, Yc, Hoover, Rn, Hosgood HD, 3rd, Hsiao, Cf, Hsing, Aw, Hsiung, Ca, Hu, N, Hu, W, Hu, Z, Huang, M, Hunter, Dj, Inskip, Pd, Ito, H, Jacobs, Ej, Jacobs, Kb, Jenab, M, Ji, Bt, Johansen, C, Johansson, M, Johnson, A, Kaaks, R, Kamat, Am, Kamineni, A, Karagas, M, Khanna, C, Khaw, Kt, Kim, C, Kim, I, Kim, Yh, Kim, Yc, Kim, Yt, Kang, Ch, Jung, Yj, Kitahara, Cm, Klein, Ap, Klein, R, Kogevinas, M, Koh, Wp, Kohno, T, Kolonel, Ln, Kooperberg, C, Kratz, Cp, Krogh, V, Kunitoh, H, Kurtz, Rc, Kurucu, N, Lan, Q, Lathrop, M, Lau, Cc, Lecanda, F, Lee, Km, Lee, Mp, Le Marchand, L, Lerner, Sp, Li, D, Liao, Lm, Lim, Wy, Lin, D, Lin, J, Lindstrom, S, Linet, M, Lissowska, J, Liu, J, Ljungberg, B, Lloreta, J, Lu, D, Ma, J, Malats, N, Mannisto, S, Marina, N, Mastrangelo, G, Matsuo, K, Mcglynn, Ka, McKean Cowdin, R, Mcneill, Lh, Mcwilliams, Rr, Melin, B, Meltzer, P, Mensah, Je, Miao, X, Michaud, D, Mondul, Am, Moore, Le, Muir, K, Niwa, S, Olson, Sh, Orr, N, Panico, Salvatore, Park, Jy, Patel, Av, Patino Garcia, A, Pavanello, S, Peeters, Ph, Peplonska, B, Peters, U, Petersen, Gm, Picci, P, Pike, Mc, Porru, S, Prescott, J, Pu, X, Purdue, Mp, Qiao, Yl, Rajaraman, P, Riboli, E, Risch, Ha, Rodabough, Rj, Rothman, N, Ruder, Am, Ryu, J, Sanson, M, Schned, A, Schumacher, Fr, Schwartz, Ag, Schwartz, Kl, Schwenn, M, Scotlandi, K, Seow, A, Serra, C, Serra, M, Sesso, Hd, Severi, G, Shen, H, Shen, M, Shete, S, Shiraishi, K, Shu, Xo, Siddiq, A, Sierrasesumaga, L, Sierri, S, Loon Sihoe, Ad, Silverman, Dt, Simon, M, Southey, Mc, Spector, L, Spitz, M, Stampfer, M, Stattin, P, Stern, Mc, Stevens, Vl, Stolzenberg Solomon, Rz, Stram, Do, Strom, S, Su, Wc, Sund, M, Sung, Sw, Swerdlow, A, Tan, W, Tanaka, H, Tang, W, Tang, Zz, Tardon, A, Tay, E, Taylor, Pr, Tettey, Y, Thomas, Dm, Tirabosco, R, Tjonneland, A, Tobias, G, Toro, Jr, Travis, Rc, Trichopoulos, D, Troisi, R, Truelove, A, Tsai, Yh, Tucker, Ma, Tumino, R, Van Den Berg, D, Van Den Eeden, Sk, Vermeulen, R, Vineis, P, Visvanathan, K, Vogel, U, Wang, C, Wang, J, Wang, S, Weiderpass, E, Weinstein, Sj, Wentzensen, N, Wheeler, W, White, E, Wiencke, Jk, Wolk, A, Wolpin, Bm, Wong, Mp, Wrensch, M, Wu, C, Wu, T, Wu, X, Wu, Yl, Wunder, J, Xiang, Yb, Xu, J, Yang, Hp, Yang, Pc, Yatabe, Y, Ye, Y, Yeboah, Ed, Yin, Z, Ying, C, Yu, Cj, Yu, K, Yuan, Jm, Zanetti, Ka, Zeleniuch Jacquotte, A, Zheng, W, Zhou, B, Mirabello, L, Savage, Sa, Kraft, P, Chanock, Sj, Yeager, M, Landi, Mt, Shi, J, Chatterjee, N, Amundadottir, Lt, Wang, Z., Zhu, B., Zhang, M., Parikh, H., Jia, J., Chung, C.C., Sampson, J.N., Hoskins, J.W., Hutchinson, A., Burdette, L., Ibrahim, A., Hautman, C., Raj, P.S., Abnet, C.C., Adjei, A.A., Ahlbom, A., Albanes, D., Allen, N.E., Ambrosone, C.B., Aldrich, M., Amiano, P., Amos, C., Andersson, U., Gerald Andriole, G.A., Jr., Andrulis, I.L., Arici, C., Arslan, A.A., Austin, M.A., Baris, D., Barkauskas, D.A., Bassig, B.A., Freeman, L.E.B., Berg, C.D., Berndt, S.I., Bertazzi, P.A., Biritwum, R.B., Black, A., Blot, W., Boeing, H., Boffetta, P., Bolton, K., Boutron-Ruault, M.-C., Bracci, P.M., Brennan, P., Brinton, L.A., Brotzman, M., Bueno-de-Mesquita, H.B., Buring, J.E., Butler, M.A., Cai, Q., Cancel-Tassin, G., Canzian, F., Cao, G., Caporaso, N.E., Carrato, A., Carreon, T., Carta, A., Chang, G.-C., Chang, I.-S., Chang-Claude, J., Che, X., Chen, C.-J., Chen, C.-Y., Chen, C.-H., Chen, C., Chen, K.-Y., Chen, Y.-M., Chokkalingam, A.P., Chu, L.W., Clavel-Chapelon, F., Colditz, G.A., Colt, J.S., Conti, D., Cook, M.B., Cortessis, V.K., Crawford, E.D., Cussenot, O., Davis, F.G., De Vivo, I., Deng, X., Ding, T., Dinney, C.P., Di Stefano, A.L., Diver, W.R., Duell, E.J., Elena, J.W., Fan, J.-H., Feigelson, H.S., Feychting, M., Figueroa, J.D., Flanagan, A.M., Fraumeni, J.F., Jr., Freedman, N.D., Fridley, B.L., Fuchs, C.S., Gago-Dominguez, M., Gallinger, S., Gao, Y.-T., Gapstur, S.M., Garcia-Closas, M., Garcia-Closas, R., Gastier-Foster, J.M., Gaziano, J.M., Gerhard, D.S., Giffen, C.A., Giles, G.G., Gillanders, E.M., Giovannucci, E.L., Goggins, M., Gokgoz, N., Goldstein, A.M., Gonzalez, C., Gorlick, R., Greene, M.H., Gross, M., Grossman, H.B., Grubb, R., III and Gu, J., Guan, P., Haiman, C.A., Hallmans, G., Hankinson, S.E., Harris, C.C., Hartge, P., Hattinger, C., Hayes, R.B., He, Q., Helman, L., Henderson, B.E., Henriksson, R., Hoffman-Bolton, J., Hohensee, C., Holly, E.A., Hong, Y.-C., Hoover, R.N., Dean Hosgood, H., Hsiao, C.-F., Hsing, A.W., Hsiung, C.A., Hu, N., Hu, W., Hu, Z., Huang, M.-S., Hunter, D.J., Inskip, P.D., Ito, H., Jacobs, E.J., Jacobs, K.B., Jenab, M., Ji, B.-T., Johansen, C., Johansson, M., Johnson, A., Kaaks, R., Kamat, A.M., Kamineni, A., Karagas, M., Khanna, C., Khaw, K.-T., Kim, C., Kim, I.-S., Kim, J.H., Kim, Y.H., Kim, Y.-C., Kim, Y.T., Kang, C.H., Jung, Y.J., Kitahara, C.M., Klein, A.P., Klein, R., Kogevinas, M., Koh, W.-P., Kohno, T., Kolonel, L.N., Kooperberg, C., Kratz, C.P., Krogh, V., Kunitoh, H., Kurtz, R.C., Kurucu, N., Lan, Q., Lathrop, M., Lau, C.C., Lecanda, F., Lee, K.-M., Lee, M.P., Marchand, L.L., Lerner, S.P., Li, D., Liao, L.M., Lim, W.-Y., Lin, D., Lin, J., Lindstrom, S., Linet, M.S., Lissowska, J., Liu, J., Ljungberg, B., Lloreta, J., Lu, D., Ma, J., Malats, N., Mannisto, S., Marina, N., Mastrangelo, G., Matsuo, K., McGlynn, K.A., McKean-Cowdin, R., McNeil, L.H., McWilliams, R.R., Melin, B.S., Meltzer, P.S., Mensah, J.E., Miao, X., Michaud, D.S., Mondul, A.M., Moore, L.E., Muir, K., Niwa, S., Olson, S.H., Orr, N., Panico, S., Park, J.Y., Patel, A.V., Patino-Garcia, A., Pavanello, S., Peeters, P.H.M., Peplonska, B., Peters, U., Petersen, G.M., Picci, P., Pike, M.C., Porru, S., Prescott, J., Pu, X., Purdue, M.P., Qiao, Y.-L., Rajaraman, P., Riboli, E., Risch, H.A., Rodabough, R.J., Rothman, N., Ruder, A.M., Ryu, J.-S., Sanson, M., Schned, A., Schumacher, F.R., Schwartz, A.G., Schwartz, K.L., Schwenn, M., Scotlandi, K., Seow, A., Serra, C., Serra, M., Sesso, H.D., Severi, G., Shen, H., Shen, M., Shete, S., Shiraishi, K., Shu, X.-O., Siddiq, A., Sierrasesumaga, L., Sierri, S., Sihoe, A.D.L., Silverman, D.T., Simon, M., Southey, M.C., Spector, L., Spitz, M., Stampfer, M., Stattin, P., Stern, M.C., Stevens, V.L., Stolzenberg-Solomon, R.Z., Stram, D.O., Strom, S.S., Su, W.-C., Sund, M., Sung, S.W., Swerdlow, A., Tan, W., Tanaka, H., Tang, W., Tang, Z.-Z., Tardon, A., Tay, E., Taylor, P.R., Tettey, Y., Thomas, D.M., Tirabosco, R., Tjonneland, A., Tobias, G.S., Toro, J.R., Travis, R.C., Trichopoulos, D., Troisi, R., Truelove, A., Tsai, Y.-H., Tucker, M.A., Tumino, R., Van Den Berg, D., Van Den Eeden, S.K., Vermeulen, R., Vineis, P., Visvanathan, K., Vogel, U., Wang, C., Wang, J., Wang, S.S., Weiderpass, E., Weinstein, S.J., Wentzensen, N., Wheeler, W., White, E., Wiencke, J.K., Wolk, A., Wolpin, B.M., Wong, M.P., Wrensch, M., Wu, C., Wu, T., Wu, X., Wu, Y.-L., Wunder, J.S., Xiang, Y.-B., Xu, J., Yang, H.P., Yang, P.-C., Yatabe, Y., Ye, Y., Yeboah, E.D., Yin, Z., Ying, C., Yu, C.-J., Yu, K., Yuan, J.-M., Zanetti, K.A., Zeleniuch-Jacquotte, A., Zheng, W., Zhou, B., Mirabello, L., Savage, S.A., Kraft, P., Chanock, S.J., Yeager, M., Landi, M.T., Shi, J., Chatterjee, N., and Amundadottir, L.T.

Subjects
Male, SINGLE-NUCLEOTIDE POLYMORPHISM, Genome-wide association study, Epigenesis, Genetic, Gene Frequency, Molecular Biology, Genetics, Genetics (clinical), Neoplasms, Odds Ratio, Genome-wide association studies (GWAS), Telomerase, DNA METHYLATION Author Information, Association Studies Articles, General Medicine, PANCREATIC-CANCER, PROSTATE-CANCER, Neoplasm Proteins, POSTMENOPAUSAL BREAST-CANCER, TERT PROMOTER MUTATIONS, Gene Expression Regulation, Neoplastic, 2 SUSCEPTIBILITY LOCI, DNA methylation, Chromosomes, Human, Pair 5, Female, Risk, Locus (genetics), Single-nucleotide polymorphism, TERT and CLPTM1L gene, Biology, Polymorphism, Single Nucleotide, LUNG-CANCER, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Gene, Allele frequency, Alleles, Genetic association, chromosome 5p15.33, Computational Biology, Membrane Proteins, DNA Methylation, Genetic Loci, TELOMERE LENGTH, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Published
2014

40. Incidence of and risk factors for type-specific anal human papillomavirus infection among HIV-positive MSM

Author

Naomi Jay, J. Michael Berry, Jimmy T. Efird, Elizabeth A. Holly, Alexandra L. Hernandez, and Joel M. Palefsky

Subjects
Adult, Male, medicine.medical_specialty, Genotype, Immunology, Population, HIV Infections, Article, Cohort Studies, Risk-Taking, Risk Factors, medicine, Humans, Immunology and Allergy, Prospective Studies, Homosexuality, Male, Papillomaviridae, education, Prospective cohort study, Gynecology, Anus Diseases, education.field_of_study, biology, business.industry, Obstetrics, Incidence, Incidence (epidemiology), Papillomavirus Infections, HPV infection, virus diseases, Odds ratio, Middle Aged, biology.organism_classification, medicine.disease, Confidence interval, Infectious Diseases, business, Cohort study
Abstract

Objective HIV-positive MSM are at increased risk of anal human papillomavirus (HPV) infection compared with men in the general population, and little is known about the natural history of anal HPV infection in this population. The objective of this study was to determine the incidence of and risk factors for anal type-specific HPV infection. Design Prospective cohort study. Methods HIV-positive MSM were evaluated for anal HPV DNA, lifestyle factors, and sexual risk behaviors every 6 months for at least 2 years. Results The overall incidence rate of detectable type-specific anal HPV infection was 21.3 per 100 person-years [95% confidence interval (CI) 17.7-25.4] and was 13.3/100 person-years (10.5-16.6) for oncogenic HPV types. The most common incident infections were HPV 18 (3.7/100 person-years) and HPV 16 (3.5/100 person-years). An increased number of recent partners with whom the participant was the receptive partner [odds ratio (OR) 2.9 (1.6-5.1) 8+ partners vs. 0-1], an increased number of new partners in which the participant was the receptive partner [OR 1.03 (1.01-1.1) per partner], an increased number of new oral-anal contact partners in which the participant was the receptive partner [OR 1.1 (1.03-1.1) per partner], and the frequency of receptive anal intercourse [OR 1.1 (1.03-1.1) per act] all significantly increased the odds of incident HPV infection (P ≤ 0.05). Conclusion HIV-positive MSM have a high incidence of oncogenic anal HPV infection. Recent receptive anal sexual behaviors, including receptive anal intercourse and receptive oral-anal contact, are the most important risk factors for incident anal HPV infection.

Published
2014

41. Striatal Low-Threshold Spiking Interneurons Regulate Goal-Directed Learning

Author

Kyuhyun Choi, M. Felicia Davatolhagh, Marc V. Fuccillo, Luigim Vargas Cifuentes, Elizabeth N. Holly, and Opeyemi O. Alabi

Subjects
0301 basic medicine, Interneuron, Vesicular Inhibitory Amino Acid Transport Proteins, Dorsomedial striatum, Appetite, Biology, Reward processing, Mice, 03 medical and health sciences, 0302 clinical medicine, Reward, Interneurons, medicine, Animals, Learning, Calcium Signaling, Potassium Channels, Inwardly Rectifying, gamma-Aminobutyric Acid, Mice, Knockout, Extramural, General Neuroscience, Specific function, Motor control, Corpus Striatum, Electrophysiological Phenomena, 030104 developmental biology, medicine.anatomical_structure, nervous system, Conditioning, Operant, Instrumental learning, Goals, Neuroscience, 030217 neurology & neurosurgery
Abstract

Summary The dorsomedial striatum (DMS) is critically involved in motor control and reward processing, but the specific neural circuit mediators are poorly understood. Recent evidence highlights the extensive connectivity of low-threshold spiking interneurons (LTSIs) within local striatal circuitry; however, the in vivo function of LTSIs remains largely unexplored. We employed fiber photometry to assess LTSI calcium activity in a range of DMS-mediated behaviors, uncovering specific reward-related activity that is down-modulated during goal-directed learning. Using two mechanistically distinct manipulations, we demonstrated that this down-modulation of LTSI activity is critical for acquisition of novel contingencies, but not for their modification. In contrast, continued LTSI activation slowed instrumental learning. Similar manipulations of fast-spiking interneurons did not reproduce these effects, implying a specific function of LTSIs. Finally, we revealed a role for the γ-aminobutyric acid (GABA)ergic functions of LTSIs in learning. Together, our data provide new insights into this striatal interneuron subclass as important gatekeepers of goal-directed learning.

Published
2019

42. Risk Factors for Anal Human Papillomavirus Infection Type 16 Among HIV-Positive Men Who Have Sex With Men in San Francisco

Author

Alexandra L. Hernandez, Joel M. Palefsky, J. Michael Berry, Jimmy T. Efird, Elizabeth A. Holly, and Naomi Jay

Subjects
Male, Cross-sectional study, Anal Canal, men who have sex with men, Men who have sex with men, Risk Factors, Surveys and Questionnaires, HIV Seropositivity, Prevalence, 2.2 Factors relating to the physical environment, Pharmacology (medical), Prospective Studies, Aetiology, Substance Abuse, Intravenous, human papillomavirus, Prospective cohort study, Cancer, Human papillomavirus 16, education.field_of_study, Coinfection, Substance Abuse, virus diseases, Homosexuality, Middle Aged, Anal canal, female genital diseases and pregnancy complications, Substance abuse, Infectious Diseases, medicine.anatomical_structure, Anti-Retroviral Agents, Public Health and Health Services, HIV/AIDS, Intravenous, Infection, Adult, HPV, medicine.medical_specialty, anal cancer, Clinical Sciences, Population, Sexual and Gender Minorities (SGM/LGBT*), Article, Clinical Research, Virology, Internal medicine, Behavioral and Social Science, medicine, Humans, Anal cancer, MSM, Homosexuality, Male, education, Gynecology, business.industry, Prevention, Papillomavirus Infections, medicine.disease, Cross-Sectional Studies, Good Health and Well Being, Multivariate Analysis, Sexually Transmitted Infections, San Francisco, Digestive Diseases, business
Abstract

BackgroundHIV-positive men who have sex with men (MSM) are at high risk of anal cancer compared with the general population. Human papillomavirus (HPV) infection, particularly HPV 16, is causally associated with anal cancer. However, the risk factors for anal HPV 16 infection are poorly understood. We determined the prevalence and risk factors for anal HPV 16 infection in a population of HIV-positive MSM, most of whom were being treated with antiretroviral therapy.DesignCross-sectional data from the baseline visit of a 4-year prospective cohort study.MethodsThree hundred forty-eight HIV-positive MSM were recruited in San Francisco, and they received a detailed sexual behavior risk factor questionnaire. An anal swab was used to collect specimens for HPV type-specific DNA testing using L1 HPV DNA polymerase chain reaction. We used log-binomial multivariable models to determine the risk factors for anal HPV 16 infection.ResultsNinety-two percent of HIV-positive MSM had at least 1 anal HPV type, 80% had at least 1 oncogenic HPV type, and 42% had HPV 16. Non-Hispanic white race and higher level of education were associated with a decreased risk of HPV 16 infection. A higher number of total male partners was associated with HPV 16 (relative risk: 1.6, 95% confidence interval 1.1 to 2.4, P = 0.01) for 201-1000 partners compared with 1-200. Injection drug use was independently associated with anal HPV 16 infection (relative risk: 1.5, 95% confidence interval 1.2 to 1.9, P = 0.003).ConclusionsThe prevalence of anal HPV infection, including HPV 16, is high in HIV-positive MSM. HIV-positive MSM should be counseled about the risk associated with increased partners and injection drug use.

Published
2013

43. Allergies and Risk of Pancreatic Cancer: A Pooled Analysis From the Pancreatic Cancer Case-Control Consortium

Author

Elizabeth T.H. Fontham, Kristin E. Anderson, Paige M. Bracci, Meier Hsu, Albert B. Lowenfels, Carlo La Vecchia, Elizabeth A. Holly, H. Bas Bueno-de-Mesquita, Emmy Ludwig, Jerry Polesel, Brian Luckett, Ersilia Lucenteforte, Bu Tian Ji, Renato Talamini, Ayelet Borgida, Michelle Cotterchio, Steven Gallinger, Robert C. Kurtz, Gloria M. Petersen, Lori S Strayer, Debra T. Silverman, Sara H. Olson, Daniela Seminara, Jaya M. Satagopan, Patrick Maisonneuve, Eric J. Duell, and Qi Dai

Subjects
Male, medicine.medical_specialty, allergic rhinitis, case-control studies, hypersensitivity, pancreatic neoplasms, Age Distribution, Aged, Asthma, Body Mass Index, Female, Humans, Hypersensitivity, Middle Aged, Pancreatic Neoplasms, Risk Factors, Sex Distribution, Smoking, Socioeconomic Factors, Epidemiology, Population, Logistic regression, Lower risk, Internal medicine, Medicine, education, education.field_of_study, business.industry, Case-control study, Odds ratio, Confidence interval, Immunology, Age of onset, business, Systematic Reviews and Meta- and Pooled Analyses, Body mass index
Abstract

In order to quantify the risk of pancreatic cancer associated with history of any allergy and specific allergies, to investigate differences in the association with risk according to age, gender, smoking status, or body mass index, and to study the influence of age at onset, we pooled data from 10 case-control studies. In total, there were 3,567 cases and 9,145 controls. Study-specific odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression adjusted for age, gender, smoking status, and body mass index. Between-study heterogeneity was assessed by using the Cochran Q statistic. Study-specific odds ratios were pooled by using a random-effects model. The odds ratio for any allergy was 0.79 (95% confidence interval (CI): 0.62, 1.00) with heterogeneity among studies (P < 0.001). Heterogeneity was attributable to one study; with that study excluded, the pooled odds ratio was 0.73 (95% CI: 0.64, 0.84) (Pheterogeneity = 0.23). Hay fever (odds ratio = 0.74, 95% CI: 0.56, 0.96) and allergy to animals (odds ratio = 0.62, 95% CI: 0.41, 0.94) were related to lower risk, while there was no statistically significant association with other allergies or asthma. There were no major differences among subgroups defined by age, gender, smoking status, or body mass index. Older age at onset of allergies was slightly more protective than earlier age.

Published
2013

44. Dietary Patterns and Risk of Pancreatic Cancer in a Large Population-Based Case-Control Study in the San Francisco Bay Area

Author

June M. Chan, Paige M. Bracci, Elizabeth A. Holly, and Zhihong Gong

Subjects
Male, Gerontology, Cancer Research, White meat, Oncology and Carcinogenesis, Population, Medicine (miscellaneous), Logistic regression, Article, Body Mass Index, Pancreatic Cancer, Rare Diseases, Risk Factors, Environmental health, Pancreatic cancer, Vegetables, 80 and over, Confidence Intervals, Odds Ratio, Humans, Medicine, Refined grains, education, Cancer, Nutrition, Aged, Aged, 80 and over, education.field_of_study, Nutrition and Dietetics, Nutrition & Dietetics, business.industry, Prevention, Case-control study, Feeding Behavior, Odds ratio, Middle Aged, medicine.disease, Pancreatic Neoplasms, Oncology, Case-Control Studies, Female, San Francisco, Digestive Diseases, business, Body mass index
Abstract

Pancreatic cancer is highly lethal, and identifying modifiable risk factors could have substantial public health impact. In this population-based case-control study (532 cases, 1701 controls), we used principal component analysis and multivariable unconditional logistic regression models to examine whether a particular dietary pattern was associated with risk of pancreatic cancer, adjusting for other known risk factors. A prudent dietary pattern, characterized by greater intake of vegetables, fruit, fish, poultry, whole grains, and low-fat dairy, was associated with an approximate 50% reduction in pancreatic cancer risk among men [odds ratio (OR) = 0.51, 95% confidence intervals (CI) = 0.31-0.84, P trend = 0.001] and women (OR = 0.51, 95% CI = 0.29-0.90, P trend = 0.04). A Western dietary pattern, characterized by higher intake of red and processed meats, potato chips, sugary beverages, sweets, high fat dairy, eggs, and refined grains, was associated with a 2.4-fold increased risk of pancreatic cancer among men (95% CI = 1.3-4.2, P trend = 0.008) but was not associated with risk among women. Among men, those in the upper quintiles of the Western diet and lower quintiles of the prudent diet had a threefold increased risk. Consistent with what has been recommended for several other chronic diseases, consuming a diet rich in plant-based foods, whole grains, and white meat, might reduce risk of pancreatic cancer.

Published
2013

45. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

Author

Edward Giovannucci, Rachael S. Stolzenberg-Solomon, Daniela Basso, Markus W. Büchler, Donghui Li, Manal M. Hassan, Niccola Funel, Mark D. Thornquist, Steven Gallinger, Andrea Z. LaCroix, Nathalia Giese, Julie E. Buring, Eric J. Jacobs, Michelle Brotzman, Philip R. Taylor, Aruna Kamineni, Neil E. Caporaso, Gabriella Andreotti, Cosmeri Rizzato, Satu Männistö, Timothy J. Key, Howard D. Sesso, Paige M. Bracci, Eric A. Klein, Renata Talar-Wojnarowska, Petra H.M. Peeters, Charles Kooperberg, Patricia Hartge, Pavel Soucek, Anne Zeleniuch-Jacquotte, Anne Tjønneland, Vittorio Krogh, Herbert Yu, Jean Wactawski-Wende, Roger L. Milne, Laufey T. Amundadottir, Francisco X. Real, Sonja I. Berndt, Andrea Mambrini, Melissa A. Austin, Kathy J. Helzlsouer, Miquel Porta, Rudolf Kaaks, Wei Zheng, Richard Barfield, Robert C. Kurtz, Alan A. Arslan, Ulrike Peters, Matthew H. Kulke, Federico Canzian, Maria Teresa Landi, Charles S. Fuchs, H. Bas Bueno-de-Mesquita, Nathaniel Rothman, Stephen J. Chanock, Kouros Owzar, Debra T. Silverman, Kai Yu, Harvey A. Risch, Daniele Campa, Marie-Christine Boutron-Ruault, Juozas Kupcinskas, Ann L. Oberg, Manolis Kogevinas, Laurie Burdette, Laurence N. Kolonel, Michelle Cotterchio, Robert N. Hoover, Núria Malats, Malin Sund, Megan J. Gorman, Raffaele Pezzilli, Peter Bugert, Nicolas Wentzensen, Myron D. Gross, Geoffrey S. Tobias, Pavel Vodicka, Dimitrios Trichopoulos, Charles C. Chung, Stefano Landi, Nan Hu, Gary E. Goodman, Emily White, Christopher A. Haiman, J. Michael Gaziano, Phyllis J. Goodman, Kala Visvanathan, Loic Le Marchand, George Theodoropoulos, Christian C. Abnet, Yusuke Nakamura, Alison P. Klein, Gabriele Capurso, Eric J. Duell, Zhaoming Wang, Federico Innocenti, Gloria M. Petersen, Xiao-Ou Shu, Chen Wu, Kay-Tee Khaw, Mazda Jenab, Graham G. Giles, Laura Beane-Freeman, Brian E. Henderson, Elio Riboli, Michael Goggins, Eithne Costello, David J. Hunter, Alpa V. Patel, Sara H. Olson, Aldo Scarpa, Brian M. Wolpin, Demetrius Albanes, Peter Kraft, Joanne W. Elena, Elizabeth A. Holly, and Ada Piepoli

Subjects
Male, Linkage disequilibrium, multistage genome-wide association study, pancreatic cancer, Genotype, European Continental Ancestry Group, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, White People, Pancreatic cancer, Genetics, medicine, Humans, Aged, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Middle Aged, Pancreatic Neoplasms, Genetic Loci, Polymorphism, Càncer de pàncrees, Pancreas cancer, Case-control study, Single Nucleotide, Genomics, Odds ratio, medicine.disease, Molecular biology, Confidence interval, 3. Good health, Genòmica
Abstract

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 x 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 x 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 x 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 x 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 x 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 x 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

Published
2016

46. Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region

Author

Joseph Vijai, W. Ryan Diver, Degui Zhi, Brenda M. Birmann, Henrik Hjalgrim, Bruce K. Armstrong, Gianluca Severi, Pierluigi Cocco, Joseph F. Fraumeni, Xifeng Wu, Graham G. Giles, Eleanor Kane, Herve Ghesquieres, Eve Roman, Edward Giovannucci, Mads Melbye, Rudolph Kaaks, Lindsay M. Morton, Nicholas K. Akers, Elizabeth A. Holly, Liming Liang, Patrizio Mazza, Kari E. North, John J. Spinelli, Carrie A. Thompson, Bodil Ohlsson, Yuanqing Ye, Anneclaire J. De Roos, Stephen J. Chanock, Theodore R. Holford, Paul Brennan, Jianjun Liu, Roel Vermeulen, Thomas E. Witzig, Angela Brooks-Wilson, Mark P. Purdue, Ahmet Dogan, Gilles Salles, Kenneth Offit, Lucia Conde, Laurie Burdett, George J. Weiner, Anne Kricker, James McKay, Peter Kraft, Sonja I. Berndt, Attilio Gabbas, Rebecca Montalvan, Rebecca D. Jackson, Baoshan Ma, Zhaoming Wang, Patricia Hartge, Danylo J. Villano, Marc Maynadie, Mortimer J. Lacher, Lauren R. Teras, Susan L. Slager, Lenka Foretova, Rachel S. Kelly, Martha S. Linet, Brian K. Link, Jarmo Virtamo, Charles C. Chung, Anne Zeleniuch-Jacquotte, Martyn T. Smith, Tracy Lightfoot, Jacques Riby, Paolo Boffetta, Meredith Yeager, Brian C.-H. Chiu, Grzegorz S. Nowakowski, Yolanda Benavente, Bengt Glimelius, Mark Liebow, Saioa Chamosa, Charles E. Lawrence, Karin E. Smedby, Nikolaus Becker, Thomas M. Habermann, Jacqueline Clavel, Qing Lan, Alexandra Nieters, Maryjean Schenk, Sophia S. Wang, Demetrius Albanes, Lesley F. Tinker, Alex Smith, Anthony Staines, Amy Hutchinson, Wendy Cozen, Hans-Olov Adami, Anne J. Novak, Christine F. Skibola, Ann Maria, Elisabete Weiderpass, Kimberly A. Bertrand, James R. Cerhan, Maria Grazia Ennas, Claire M. Vajdic, Jinyan Huang, Paul I.W. de Bakker, Paige M. Bracci, Tongzhang Zheng, Ruth C. Travis, Paolo Vineis, Jia Nee Foo, Jennifer Turner, Alain Monnereau, Silvia de Sanjosé, Nathaniel Rothman, Yawei Zhang, Jian Gu, Skibola, C.F., Berndt, S.I., Vijai, J., Conde, L., Wang, Z., Yeager, M., De Bakker, P.I.W., Birmann, B.M., Vajdic, C.M., Foo, J.-N., Bracci, P.M., Vermeulen, R.C.H., Slager, S.L., De Sanjose, S., Wang, S.S., Linet, M.S., Salles, G., Lan, Q., Severi, G., Hjalgrim, H., Lightfoot, T., Melbye, M., Gu, J., Ghesquières, H., Link, B.K., Morton, L.M., Holly, E.A., Smith, A., Tinker, L.F., Teras, L.R., Kricker, A., Becker, N., Purdue, M.P., Spinelli, J.J., Zhang, Y., Giles, G.G., Vineis, P., Monnereau, A., Bertrand, K.A., Albanes, D., Zeleniuch-Jacquotte, A., Gabbas, A., Chung, C.C., Burdett, L., Hutchinson, A., Lawrence, C., Montalvan, R., Liang, L., Huang, J., Ma, B., Liu, J., Adami, H.-O., Glimelius, B., Ye, Y., Nowakowski, G.S., Dogan, A., Thompson, C.A., Habermann, T.M., Novak, A.J., Liebow, M., Witzig, T.E., Weiner, G.J., Schenk, M., Hartge, P., De Roos, A.J., Cozen, W., Zhi, D., Akers, N.K., Riby, J., Smith, M.T., Lacher, M., Villano, D.J., Maria, A., Roman, E., Kane, E., Jackson, R.D., North, K.E., Diver, W.R., Turner, J., Armstrong, B.K., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., McKay, J., Brooks-Wilson, A.R., Zheng, T., Holford, T.R., Chamosa, S., Kaaks, R., Kelly, R.S., Ohlsson, B., Travis, R.C., Weiderpass, E., Clavel, J., Giovannucci, E., Kraft, P., Virtamo, J., Mazza, P., Cocco, P., Ennas, M.G., Chiu, B.C.H., Fraumeni, J.F., Jr., Nieters, A., Offit, K., Wu, X., Cerhan, J.R., Smedby, K.E., Chanock, S.J., and Rothman, N.

Subjects
EXPRESSION, Follicular lymphoma, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Biology, VARIANTS, Polymorphism, Single Nucleotide, follicular lymphoma, HLA Antigens, Polymorphism (computer science), Report, CLASS-I, RESOURCE, Biomarkers, Tumor, Genetics, medicine, Chromosomes, Human, Humans, TOOL, Genetic Predisposition to Disease, Genetics(clinical), PEPTIDE, Allele, Lymphoma, Follicular, Alleles, Genetics (clinical), Genetic association, SNPS, RISK, Genome-wide association, Haplotype, medicine.disease, HLA, Haplotypes, Case-Control Studies, UNIVERSITY, SET, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10 -20) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10 -11) near ETS1; 3q28 (rs6444305, p = 1.10 × 10 -10) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10 -10) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10 -8) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRß1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10 -67 to 2.67 × 10 -70). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10 -16) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10 -9). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk. © 2014 by The American Society of Human Genetics. All rights reserved.

Published
2016

47. Maladaptive choices by defeated rats: link between rapid approach to social threat and escalated cocaine self-administration

Author

Elizabeth N. Holly, Klaus A. Miczek, Joseph F. DeBold, Andrew R. Burke, Christopher O. Boyson, and Sandra Montagud-Romero

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Corticotropin-Releasing Hormone, Individuality, Self Administration, Tropomyosin receptor kinase B, Impulsivity, Choice Behavior, Open field, Article, Social defeat, 03 medical and health sciences, Cocaine-Related Disorders, 0302 clinical medicine, Saccharin, Extended amygdala, Cocaine, Dopamine Uptake Inhibitors, medicine, Animals, Rats, Long-Evans, Psychiatry, Social Behavior, Pharmacology, Principal Component Analysis, Behavior, Animal, Aggression, Novelty, Rats, 030104 developmental biology, Sweetening Agents, medicine.symptom, Psychology, Self-administration, Corticosterone, Neuroscience, 030217 neurology & neurosurgery, Stress, Psychological
Abstract

Intermittent social defeat stress engenders persistent neuroadaptations and can result in later increased cocaine taking and seeking. However, there are individual differences in stress-escalated cocaine self-administration behavior, which may be a direct result of individual differences in the manner in which rats experience social defeat stress. The present study dissected the discrete behavioral phases of social defeat and analyzed which behavioral characteristics may be predictive of subsequent cocaine self-administration. Male Long-Evans rats underwent nine intermittent social defeat episodes over 21 days in a three-compartment apparatus permitting approach to and escape from a confrontation with an aggressive resident rat. Rats then self-administered intravenous cocaine, which culminated in a 24-h unlimited access “binge.” Behaviors during social defeat and cocaine self-administration were evaluated by principal component analysis (PCA). PCA revealed that the latency to enter the threatening environment was highly predictive of later cocaine self-administration during the 24-h binge. This behavior was not associated with other cocaine-predictive traits, such as reactivity to novelty in an open field, saccharin preference, and motor impulsivity. Additionally, there was no effect of latency to enter a threatening environment on physiological measures of stress, including plasma corticosterone and corticotropin releasing factor (CRF) in the extended amygdala. However, latency to enter the threatening environment was negatively correlated with brain-derived neurotropic factor (BDNF) and its receptor, tyrosine kinase B (TrkB) in the hippocampus. These data suggest that latency to enter a threatening environment is a novel behavioral characteristic predictive of later cocaine self-administration.

Published
2016

48. Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes

Author

Henrik Hjalgrim, Joseph Vijai, Bengt Glimelius, Kimberly A. Bertrand, Immaculata De Vivo, Eve Roman, Martha Glenn, Nathaniel Rothman, Yolanda Benavente, Zhaoming Wang, Ju-Hyun Park, Anneclaire J. De Roos, John J. Spinelli, Demetrius Albanes, Paul Brennan, Emanuele Angelucci, Mariagrazia Zucca, Qing Lan, Kari E. North, Paige M. Bracci, Mark P. Purdue, Marco Rais, Melissa C. Southey, Alain Monnereau, Ahmet Dogan, Graham G. Giles, Robert J. Klein, Peter Kraft, Lesley F. Tinker, Laurie Burdett, Lucia Conde, Carrie A. Thompson, James McKay, Martyn T. Smith, Göran Roos, Yan W. Asmann, Dennis D. Weisenburger, Elizabeth A. Holly, Thomas E. Witzig, Liming Liang, Paul I.W. de Bakker, Alex Smith, Jarmo Virtamo, Charles E. Lawrence, Patricia Hartge, Karen Curtin, Anthony Staines, Nikolaus Becker, Nicola J. Camp, Charles C. Chung, Degui Zhi, Brenda M. Birmann, W. Ryan Diver, Roel Vermeulen, Sonja I. Berndt, Tongzhang Zheng, Silvia de Sanjosé, Eleanor Kane, James R. Cerhan, Christopher R. Flowers, Joseph F. Fraumeni, Stephen J. Chanock, Stephen M. Ansell, Angela Brooks-Wilson, Kenneth Offit, Jinyan Huang, Mads Melbye, Edward Giovannucci, Baoshan Ma, Tracy Lightfoot, Brian K. Link, Richard K. Severson, Theodore R. Holford, Yawei Zhang, Anne Tjønneland, Meredith Yeager, Wendy Cozen, Anne J. Novak, Lauren R. Teras, Claire M. Vajdic, Lisa A. Cannon-Albright, Lenka Foretova, Christine F. Skibola, Sophia S. Wang, Hans-Olov Adami, Andrew D. Zelenetz, Jenny Turner, Paolo Vineis, Corinne Haioun, Hervé Tilly, Anne Zeleniuch-Jacquotte, Thomas M. Habermann, Paolo Boffetta, Jacqueline Clavel, Herve Ghesquieres, Stephanie J. Weinstein, Lindsay M. Morton, Susan L. Slager, Simon Crouch, Gilles Salles, Rachel S. Kelly, Karin E. Smedby, Amy Hutchinson, David G. Cox, Elio Riboli, Jacques Riby, Rebecca D. Jackson, Mark Liebow, Thierry Jo Molina, Danylo J. Villano, Marc Maynadie, Yuanqing Ye, Heiner Boeing, Jian Gu, Brian C.-H. Chiu, Simonetta Di Lollo, Mitchell J. Machiela, Alexandra Nieters, Xifeng Wu, Rudolph Kaaks, Machiela, M.J., Lan, Q., Slager, S.L., Vermeulen, R.C.H., Teras, L.R., Camp, N.J., Cerhan, J.R., Spinelli, J.J., Wang, S.S., Nieters, A., Vijai, J., Yeager, M., Wang, Z., Ghesquières, H., McKay, J., Conde, L., de Bakker, P.I.W., Cox, D.G., Burdett, L., Monnereau, A., Flowers, C.R., De Roos, A.J., Brooks-Wilson, A.R., Giles, G.G., Melbye, M., Gu, J., Jackson, R.D., Kane, E., Purdue, M.P., Vajdic, C.M., Albanes, D., Kelly, R.S., Zucca, M., Bertrand, K.A., Zeleniuch-Jacquotte, A., Lawrence, C., Hutchinson, A., Zhi, D., Habermann, T.M., Link, B.K., Novak, A.J., Dogan, A., Asmann, Y.W., Liebow, M., Thompson, C.A., Ansell, S.M., Witzig, T.E., Tilly, H., Haioun, C., Molina, T.J., Hjalgrim, H., Glimelius, B., Adami, H.-O., Roos, G., Bracci, P.M., Riby, J., Smith, M.T., Holly, E.A., Cozen, W., Hartge, P., Morton, L.M., Severson, R.K., Tinker, L.F., North, K.E., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., Lightfoot, T., Crouch, S., Smith, A., Roman, E., Ryan Diver, W., Offit, K., Zelenetz, A., Klein, R.J., Villano, D.J., Zheng, T., Zhang, Y., Holford, T.R., Turner, J., Southey, M.C., Clavel, J., Virtamo, J., Weinstein, S., Riboli, E., Vineis, P., Kaaks, R., Boeing, H., Tjønneland, A., Angelucci, E., Di Lollo, S., Rais, M., De Vivo, I., Giovannucci, E., Kraft, P., Huang, J., Ma, B., Ye, Y., Chiu, B.C.H., Liang, L., Park, J.-H., Chung, C.C., Weisenburger, D.D., Fraumeni, J.F., Jr and Salles, G., Glenn, M., Cannon-Albright, L., Curtin, K., Wu, X., Smedby, K.E., de Sanjose, S., Skibola, C.F., Berndt, S.I., Birmann, B.M., Chanock, S.J., Rothman, N., LS IRAS EEPI GRA (Gezh.risico-analyse), Sub Atmospheric physics and chemistry, dIRAS RA-I&I RA, dIRAS RA-2, Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Cancer environnement ( EPICENE ), Bordeaux population health ( BPH ), Université de Bordeaux ( UB ) -Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bordeaux ( UB ) -Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Registre des hémopathies malignes de la Gironde, Institut Bergonié - CRLCC Bordeaux, Department of Agronomy, University of Wisconsin-Madison [Madison], Service hématologie Poitiers, CHU, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris Descartes - Paris 5 ( UPD5 ), Oslo and Akershus University College ( OAUC ), Laboratoire de mécanique Biomécanique Polymère Structures ( LaBPS ), Université de Lorraine ( UL ), The Tisch Cancer Institute, Mount Sinai School of Medicine, International Agency for Cancer Research ( IACR ), International Agency for Cancer Research, Registre des hémopathies malignes de Côte d'Or, Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), University of Chicago Medicine, Institut National de la Santé et de la Recherche Médicale ( INSERM ), French National Registry of Childhood Hematological malignancies (NRCH), NRCH, Division of Epidemiology, Public Health and Primary Care, Imperial College London, Unit of Cancer Epidemiology, AOU S. Giovanni Battista, CPO Piemonte, CeRMS, University of Torino, Department of Epidemiology and Public Health, Department Cancer Epidemiology, German Cancer Research Center, Institute of Human Nutrition Potsdam-Rehbruecke, Diet, Cancer and Health, Danish Cancer Society, Justus Liebig University Giessen, Sino French Research Center for Biomedical Imaging ( HIT-INSA ), Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Harbin Institute of Technology ( HIT ), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ), Institut de Physique Nucléaire d'Orsay ( IPNO ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Chinese Academy of Sciences [Beijing] ( CAS ), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer environnement (EPICENE ), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, University of Wisconsin-Madison, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Descartes - Paris 5 (UPD5), Akershus University College, Laboratoire de mécanique Biomécanique Polymère Structures (LaBPS), Université de Lorraine (UL), Icahn School of Medicine at Mount Sinai [New York] (MSSM), International Agency for Cancer Research (IACR), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut National de la Santé et de la Recherche Médicale (INSERM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Justus-Liebig-Universität Gießen (JLU), Sino French Research Center for Biomedical Imaging (HIT-INSA), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Harbin Institute of Technology (HIT), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chinese Academy of Sciences [Beijing] (CAS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Harbin Institute of Technology (HIT), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Oslo and Akershus University College (OAUC), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
0301 basic medicine, Serum, Male, Lymphoma, analysis, Chronic lymphocytic leukemia, Follicular lymphoma, Global Health, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, immunology, surgery, 0302 clinical medicine, Endocrinology, immune system diseases, single nucleotide polymorphism, Germany, hemic and lymphatic diseases, London, 80 and over, Odds Ratio, genetics, Prospective Studies, B-cell lymphoma, Association Studies Article, Genetics (clinical), Aged, 80 and over, education.field_of_study, telomere, Genome, Leukemia, Age Factors, General Medicine, Environmental exposure, Genomics, Middle Aged, b-cell lymphoma, small cell lymphoma, Italy, 030220 oncology & carcinogenesis, Medicine, epidemiology, Female, France, Risk of B-cell lymphoma subtypes, Risk, Adult, Canada, China, Lymphoma, B-Cell, Genotype, Adolescent, leukocytes, etiology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Environment, Risk Assessment, methods, Time, 03 medical and health sciences, medicine, Humans, Family, Genetic Predisposition to Disease, education, Molecular Biology, Alleles, Occupational Health, Genetic Association Studies, Aged, B-Cell, International Agencies, Odds ratio, Environmental Exposure, medicine.disease, Telomere, Non-Hodgkin's lymphoma, 030104 developmental biology, Immunology, physiology, Chronic Disease, pathology, Laboratories, metabolism
Abstract

International audience; Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk

Published
2016

49. Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area

Author

Sandra Montagud-Romero, Elizabeth N. Holly, Dirson João Stein, Klaus A. Miczek, Kyle L. Gobrogge, Joseph F. DeBold, Christopher O. Boyson, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research at MIT, and Holly, Elizabeth N

Subjects
Male, medicine.medical_specialty, endocrine system, Corticotropin-Releasing Hormone, Microdialysis, Drug-Seeking Behavior, Neuropeptide, Self Administration, Nucleus accumbens, Social Environment, Receptors, Corticotropin-Releasing Hormone, Social defeat, 03 medical and health sciences, Corticotropin-releasing hormone, Cocaine-Related Disorders, 0302 clinical medicine, Dopamine, Internal medicine, mental disorders, medicine, Animals, Rats, Long-Evans, Social stress, General Neuroscience, musculoskeletal, neural, and ocular physiology, Dopaminergic, Ventral Tegmental Area, Articles, 030227 psychiatry, Rats, Substance Withdrawal Syndrome, Ventral tegmental area, medicine.anatomical_structure, Endocrinology, nervous system, Psychology, Neuroscience, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Stress, Psychological, medicine.drug
Abstract

Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats.In vivomicrodialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h “binge.” VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2.SIGNIFICANCE STATEMENTCorticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction.

Published
2016

50. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

Author

Christian C. Abnet, Chen Wu, Edward Giovannucci, Federico Canzian, Robert R. McWilliams, Kay-Tee Khaw, Amy Hutchinson, Alison P. Klein, Mark P. Purdue, Laurence N. Kolonel, Neil E. Caporaso, Elio Riboli, Lauren R. Teras, William J. Blot, Andrea Z. LaCroix, Philip R. Taylor, Amanda Black, Jay S. Wunder, Belynda Hicks, Ana Patiño-García, Emily White, Maria Pik Wong, Nicolas Wentzensen, Yi-Long Wu, Caroline G. Epstein, Fredrick R. Schumacher, Avima M. Ruder, David Van Den Berg, Chao A. Hsiung, Meredith Yeager, Maria Teresa Landi, Susan M. Gapstur, Kari G. Chaffee, Krista A. Zanetti, Louise A. Brinton, Lingeng Lu, Robert C. Kurtz, Beatrice Melin, Cathryn H. Bock, Núria Malats, Veronica Wendy Setiawan, Montserrat Garcia-Closas, Christopher A. Haiman, Yu-Tang Gao, Jennifer A. Doherty, Roger Henriksson, Jennifer Prescott, Lee E. Moore, Jianjun Liu, You-Lin Qiao, Lynn R. Goldin, Wei Hu, Christopher I. Amos, Kala Visvanathan, Xifeng Wu, Constance Chen, Charles C. Chung, Nan Hu, Min-Ho Shin, Preetha Rajaraman, Christoffer Johansen, Robert J. Klein, Gloria M. Petersen, Hee Nam Kim, Lucy Xia, Anne Zeleniuch-Jacquotte, Xin Sheng, Faith G. Davis, Göran Hallmans, Xiao-Ou Shu, Harvey A. Risch, Regina G. Ziegler, Kai Yu, Chu Chen, Alisa M. Goldstein, Elizabeth A. Holly, Beata Peplonska, Sharon A. Savage, J. Michael Gaziano, Daniel O. Stram, Yeul Hong Kim, Laurie Burdett, Sonja I. Berndt, Hannah P. Yang, Graham G. Giles, Laufey T. Amundadottir, Casey L. Dagnall, Weiyin Zhou, Sholom Wacholder, Mazda Jenab, Charles S. Fuchs, Nathaniel Rothman, Tania Carreón, H. Bas Bueno-de-Mesquita, Anthony M. Magliocco, Stephen J. Chanock, Qi Yang, Robert N. Hoover, Mary Ann Butler, Ulrike Peters, Kexin Chen, Charles Kooperberg, Linda M. Liao, Jae Yong Park, Loreall Pooler, Adeline Seow, Elizabeth M. Gillanders, Alan A. Arslan, Peter Kraft, Christine M. Friedenreich, Michael Cullen, Rachael Z. Stolzenberg-Solomon, Eric J. Duell, Laura Beane-Freeman, Dongxin Lin, Yun-Chul Hong, Gianluca Severi, Baosen Zhou, Mitchell J. Machiela, Luis A. Pérez-Jurado, Ludmila Prokunina-Olsson, Xiaolin Liang, Susan E. Hankinson, Steven Gallinger, Paige M. Bracci, Marta Crous Bou, Jiucun Wang, Jolanta Lissowska, Benjamín Rodríguez-Santiago, Young Tae Kim, Pan-Chyr Yang, Ann G. Schwartz, Lisa Mirabello, Jin-Hu Fan, Hongbing Shen, Keitaro Matsuo, Mia M. Gaudet, Neal D. Freedman, Zhaoming Wang, John K. Wiencke, Woon-Puay Koh, Margaret A. Tucker, Ti Ding, Linda S. Cook, Geoffrey S. Tobias, Irene Orlow, Lorna H. McNeill, Ze Zhong Tang, Francisco X. Real, Christopher Hautman, Donghui Li, Qing Lan, Julie E. Buring, Eric Karlins, Tangchun Wu, Curtis C. Harris, Joseph F. Fraumeni, Immaculata De Vivo, I. Shou Chang, Vittorio Krogh, Michael Dean, Kevin B. Jacobs, Debra T. Silverman, Jonine D. Figueroa, Nilanjan Chatterjee, Margaret R. Spitz, William Wheeler, David J. Hunter, Melinda C. Aldrich, Wei Zheng, Sara H. Olson, Kendra Schwartz, Victoria L. Stevens, Joshua N. Sampson, Brian M. Wolpin, Loic Le Marchand, National High-Tech Research and Development Program (China), Fred Hutchinson Cancer Research Center, Fudan Lung Cancer Study Ministry of Health, National Science Foundation (China), Agency for Science, Technology and Research (Singapur), National Science Council, Taiwan, National Institutes of Health (Estados Unidos), National Research Foundation of Korea, and Ministry of Science, ICT and Future Planning (Korea)

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Aging, BLOOD, SOMATIC MOSAICISM, Science, General Physics and Astronomy, Biology, HEMATOPOIESIS, Polymerase Chain Reaction, Article, General Biochemistry, Genetics and Molecular Biology, X-inactivation, 03 medical and health sciences, X Chromosome Inactivation, MD Multidisciplinary, medicine, HUMAN GENOME, Humans, MUTATION, Cancer genetics, X chromosome, Genetic association, Genetics, Chromosomes, Human, X, Science & Technology, Multidisciplinary, Autosome, ANEUPLOIDIES, Mosaicism, METHYLATION, Chromosome, Reproducibility of Results, General Chemistry, DNA Methylation, CANCER, 3. Good health, Multidisciplinary Sciences, 030104 developmental biology, DETECTABLE CLONAL MOSAICISM, CELLS, Science & Technology - Other Topics, Medical genetics, Human genome, Female, SNP array
Abstract

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases., It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk

Published
2016

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