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1. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Author

Pooja Middha, Xiaoliang Wang, Sabine Behrens, Manjeet K. Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Annelie Augustinsson, Thaïs Baert, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Javier Benitez, Stig E. Bojesen, Hiltrud Brauch, Hermann Brenner, Angela Brooks-Wilson, Daniele Campa, Federico Canzian, Angel Carracedo, Jose E. Castelao, Stephen J. Chanock, Georgia Chenevix-Trench, CTS Consortium, Emilie Cordina-Duverger, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Laure Dossus, Pierre-Antoine Dugué, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Olivia Fletcher, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Graham G. Giles, Anna González-Neira, Felix Grassmann, Anne Grundy, Pascal Guénel, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Susan E. Hankinson, Elaine F. Harkness, Bernd Holleczek, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, David J. Hunter, Christian Ingvar, ABCTB Investigators, kConFab Investigators, Karolin Isaksson, Helena Jernström, Esther M. John, Michael E. Jones, Rudolf Kaaks, Renske Keeman, Cari M. Kitahara, Yon-Dschun Ko, Stella Koutros, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Nicole L. Larson, Susanna Larsson, Loic Le Marchand, Flavio Lejbkowicz, Shuai Li, Martha Linet, Jolanta Lissowska, Maria Elena Martinez, Tabea Maurer, Anna Marie Mulligan, Claire Mulot, Rachel A. Murphy, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Katie M. O’Brien, Janet E. Olson, Alpa V. Patel, Ross Prentice, Erika Rees-Punia, Gad Rennert, Valerie Rhenius, Kathryn J. Ruddy, Dale P. Sandler, Christopher G. Scott, Mitul Shah, Xiao-Ou Shu, Ann Smeets, Melissa C. Southey, Jennifer Stone, Rulla M. Tamimi, Jack A. Taylor, Lauren R. Teras, Katarzyna Tomczyk, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Sophia S. Wang, Clarice R. Weinberg, Hans Wildiers, Walter Willett, Stacey J. Winham, Alicja Wolk, Xiaohong R. Yang, M. Pilar Zamora, Wei Zheng, Argyrios Ziogas, Alison M. Dunning, Paul D. P. Pharoah, Montserrat García-Closas, Marjanka K. Schmidt, Peter Kraft, Roger L. Milne, Sara Lindström, Douglas F. Easton, and Jenny Chang-Claude

Subjects
Breast cancer, Gene-environment interactions, Genetic epidemiology, European ancestry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability

Published
2023
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2. Accelerated epigenetic aging and myopenia in young adult cancer survivors

Author

Stephanie C. Gehle, Daniel Kleissler, Hillary Heiling, Allison Deal, Zongli Xu, Vanessa L. Ayer Miller, Jack A. Taylor, and Andrew B. Smitherman

Subjects
aging, cancer survivorship, DNA methylation, epigenetic age, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Young adult cancer survivors experience early aging‐related morbidities and mortality. Biological aging biomarkers may identify at‐risk survivors and increase our understanding of mechanisms underlying this accelerated aging. Methods Using an observational study design, we cross‐sectionally measured DNA methylation‐based epigenetic age in young adult cancer survivors at a tertiary, academic state cancer hospital. Participants were a convenience sample of consecutively enrolled survivors of childhood, adolescent, and young adult cancers treated with either an anthracycline or alkylating agent, and who were at least 3 months post‐treatment. Similarly aged healthy comparators were consecutively enrolled. Cancer treatment and treatment intensity were compared to DNA methylation‐based epigenetic age and pace of aging. Results Sixty survivors (58 completing assessments, mean age 20.5 years, range 18–29) and 27 comparators (mean age 20 years, range 17–29) underwent DNA methylation measurement. Survivors were predominantly female (62%) and white (60%) and averaged nearly 6 years post‐treatment (range 0.2–25 years). Both epigenetic age (AgeAccelGrim: 1.5 vs. −2.4, p

Published
2023
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3. Air pollution and epigenetic aging among Black and White women in the US

Author

Sarah H. Koenigsberg, Che-Jung Chang, Jennifer Ish, Zongli Xu, Jacob K. Kresovich, Kaitlyn G. Lawrence, Joel D. Kaufman, Dale P. Sandler, Jack A. Taylor, and Alexandra J. White

Subjects
Air pollution, DNA methylation, Particulate matter, Epigenetic age, Epigenome-wide association study, Environmental sciences, GE1-350
Abstract

Background: DNA methylation-based measures of biological aging have been associated with air pollution and may link pollutant exposures to aging-related health outcomes. However, evidence is inconsistent and there is little information for Black women. Objective: We examined associations of ambient particulate matter

Published
2023
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4. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author

Stefanie H. Mueller, Alvina G. Lai, Maria Valkovskaya, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Michael Lush, Zomoruda Abu-Ful, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Annelie Augustinsson, Thais Baert, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Hermann Brenner, Sara Y. Brucker, Saundra S. Buys, Jose E. Castelao, Tsun L. Chan, Jenny Chang-Claude, Stephen J. Chanock, Ji-Yeob Choi, Wendy K. Chung, NBCS Collaborators, Sarah V. Colonna, CTS Consortium, Sten Cornelissen, Fergus J. Couch, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Laure Dossus, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Christoph Engel, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Manuela Gago-Dominguez, Yu-Tang Gao, Montserrat García-Closas, José A. García-Sáenz, Jeanine Genkinger, Aleksandra Gentry-Maharaj, Felix Grassmann, Pascal Guénel, Melanie Gündert, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Elaine F. Harkness, Patricia A. Harrington, Jaana M. Hartikainen, Mikael Hartman, Alexander Hein, Weang-Kee Ho, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, David J. Hunter, Dezheng Huo, ABCTB Investigators, Hidemi Ito, Motoki Iwasaki, Anna Jakubowska, Wolfgang Janni, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Daehee Kang, Elza K. Khusnutdinova, Sung-Won Kim, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Allison W. Kurian, Ava Kwong, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Martha Linet, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Keitaro Matsuo, Dimitrios Mavroudis, Usha Menon, Kenneth Muir, Rachel A. Murphy, Heli Nevanlinna, William G. Newman, Dieter Niederacher, Katie M. O’Brien, Nadia Obi, Kenneth Offit, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Sue K. Park, Alpa V. Patel, Achal Patel, Charles M. Perou, Julian Peto, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Nadege Presneau, Brigitte Rack, Paolo Radice, Dhanya Ramachandran, Muhammad U. Rashid, Gad Rennert, Atocha Romero, Kathryn J. Ruddy, Matthias Ruebner, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Michael O. Schneider, Christopher Scott, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xiao-Ou Shu, Jacques Simard, Harald Surowy, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Soo Hwang Teo, Lauren R. Teras, Amanda E. Toland, Rob A. E. M. Tollenaar, Diana Torres, Gabriela Torres-Mejía, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Joseph Vijai, Clarice R. Weinberg, Camilla Wendt, Robert Winqvist, Alicja Wolk, Anna H. Wu, Taiki Yamaji, Xiaohong R. Yang, Jyh-Cherng Yu, Wei Zheng, Argyrios Ziogas, Elad Ziv, Alison M. Dunning, Douglas F. Easton, Harry Hemingway, Ute Hamann, and Karoline B. Kuchenbaecker

Subjects
Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study, Medicine, Genetics, QH426-470
Abstract

Abstract Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q

Published
2023
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5. Blood DNA methylation profiles improve breast cancer prediction

Author

Jacob K. Kresovich, Zongli Xu, Katie M. O’Brien, Min Shi, Clarice R. Weinberg, Dale P. Sandler, and Jack A. Taylor

Subjects
breast cancer, breast cancer prediction, DNA methylation, risk score, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Although blood DNA methylation (DNAm) profiles are reported to be associated with breast cancer incidence, they have not been widely used in breast cancer risk assessment. Among a breast cancer case–cohort of 2774 women (1551 cases) in the Sister Study, we used candidate CpGs and DNAm estimators of physiologic characteristics to derive a methylation‐based breast cancer risk score, mBCRS. Overall, 19 CpGs and five DNAm estimators were selected using elastic net regularization to comprise mBCRS. In a test set, higher mBCRS was positively associated with breast cancer incidence, showing similar strength to the polygenic risk score (PRS) based on 313 single nucleotide polymorphisms (313 SNPs). Area under the curve for breast cancer prediction was 0.60 for self‐reported risk factors (RFs), 0.63 for PRS, and 0.63 for mBCRS. Adding mBCRS to PRS and RFs improved breast cancer prediction from 0.66 to 0.71. mBCRS findings were replicated in a nested case–control study within the EPIC‐Italy cohort. These results suggest that mBCRS, a risk score derived using blood DNAm, can be used to enhance breast cancer prediction.

Published
2022
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6. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author

Thomas U. Ahearn, Haoyu Zhang, Kyriaki Michailidou, Roger L. Milne, Manjeet K. Bolla, Joe Dennis, Alison M. Dunning, Michael Lush, Qin Wang, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Annelie Augustinsson, Adinda Baten, Heiko Becher, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Angela Brooks-Wilson, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Christine L. Clarke, NBCS Collaborators, J. Margriet Collée, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Miriam Dwek, Diana M. Eccles, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Giuseppe Floris, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Mark S. Goldberg, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Elaine F. Harkness, Bernadette A. M. Heemskerk-Gerritsen, Bernd Holleczek, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, ABCTB Investigators, kConFab/AOCS Investigators, Milena Jakimovska, Anna Jakubowska, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Saila Kauppila, Renske Keeman, Elza Khusnutdinova, Cari M. Kitahara, Yon-Dschun Ko, Stella Koutros, Vessela N. Kristensen, Ute Krüger, Katerina Kubelka-Sabit, Allison W. Kurian, Kyriacos Kyriacou, Diether Lambrechts, Derrick G. Lee, Annika Lindblom, Martha Linet, Jolanta Lissowska, Ana Llaneza, Wing-Yee Lo, Robert J. MacInnis, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Maria Elena Martinez, Catriona McLean, Alfons Meindl, Usha Menon, Heli Nevanlinna, William G. Newman, Jesse Nodora, Kenneth Offit, Håkan Olsson, Nick Orr, Tjoung-Won Park-Simon, Alpa V. Patel, Julian Peto, Guillermo Pita, Dijana Plaseska-Karanfilska, Ross Prentice, Kevin Punie, Katri Pylkäs, Paolo Radice, Gad Rennert, Atocha Romero, Thomas Rüdiger, Emmanouil Saloustros, Sarah Sampson, Dale P. Sandler, Elinor J. Sawyer, Rita K. Schmutzler, Minouk J. Schoemaker, Ben Schöttker, Mark E. Sherman, Xiao-Ou Shu, Snezhana Smichkoska, Melissa C. Southey, John J. Spinelli, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Lauren R. Teras, Mary Beth Terry, Diana Torres, Melissa A. Troester, Celine M. Vachon, Carolien H. M. van Deurzen, Elke M. van Veen, Philippe Wagner, Clarice R. Weinberg, Camilla Wendt, Jelle Wesseling, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Wei Zheng, Fergus J. Couch, Jacques Simard, Peter Kraft, Douglas F. Easton, Paul D. P. Pharoah, Marjanka K. Schmidt, Montserrat García-Closas, and Nilanjan Chatterjee

Subjects
Breast cancer, Etiologic heterogeneity, Genetic predisposition, Common breast cancer susceptibility variants, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

Published
2022
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7. Rare germline copy number variants (CNVs) and breast cancer risk

Author

Joe Dennis, Jonathan P. Tyrer, Logan C. Walker, Kyriaki Michailidou, Leila Dorling, Manjeet K. Bolla, Qin Wang, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Hermann Brenner, Jose E. Castelao, Jenny Chang-Claude, Georgia Chenevix-Trench, Christine L. Clarke, NBCS Collaborators, J. Margriet Collée, CTS Consortium, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Laure Dossus, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Montserrat García-Closas, Graham G. Giles, Anna González-Neira, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Per Hall, Antoinette Hollestelle, Reiner Hoppe, John L. Hopper, Anthony Howell, ABCTB Investigators, kConFab/AOCS Investigators, Agnes Jager, Anna Jakubowska, Esther M. John, Nichola Johnson, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Renske Keeman, Elza Khusnutdinova, Cari M. Kitahara, Yon-Dschun Ko, Veli-Matti Kosma, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Nicole L. Larson, Martha Linet, Alicja Ogrodniczak, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Taru A. Muranen, Rachel A. Murphy, Heli Nevanlinna, Janet E. Olson, Håkan Olsson, Tjoung-Won Park-Simon, Charles M. Perou, Paolo Peterlongo, Dijana Plaseska-Karanfilska, Katri Pylkäs, Gad Rennert, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Rana Shibli, Ann Smeets, Penny Soucy, Melissa C. Southey, Anthony J. Swerdlow, Rulla M. Tamimi, Jack A. Taylor, Lauren R. Teras, Mary Beth Terry, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Camilla Wendt, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Wei Zheng, Argyrios Ziogas, Jacques Simard, Alison M. Dunning, Paul D. P. Pharoah, and Douglas F. Easton

Subjects
Biology (General), QH301-705.5
Abstract

Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.

Published
2022
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8. Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women

Author

Babatunde Adedokun, Zhaohui Du, Guimin Gao, Thomas U. Ahearn, Kathryn L. Lunetta, Gary Zirpoli, Jonine Figueroa, Esther M. John, Leslie Bernstein, Wei Zheng, Jennifer J. Hu, Regina G. Ziegler, Sarah Nyante, Elisa V. Bandera, Sue A. Ingles, Michael F. Press, Sandra L. Deming-Halverson, Jorge L. Rodriguez-Gil, Song Yao, Temidayo O. Ogundiran, Oladosu Ojengbede, William Blot, Melissa A. Troester, Katherine L. Nathanson, Anselm Hennis, Barbara Nemesure, Stefan Ambs, Peter N. Fiorica, Lara E. Sucheston-Campbell, Jeannette T. Bensen, Lawrence H. Kushi, Gabriela Torres-Mejia, Donglei Hu, Laura Fejerman, Manjeet K. Bolla, Joe Dennis, Alison M. Dunning, Douglas F. Easton, Kyriaki Michailidou, Paul D. P. Pharoah, Qin Wang, Dale P. Sandler, Jack A. Taylor, Katie M. O’Brien, Cari M. Kitahara, Adeyinka G. Falusi, Chinedum Babalola, Joel Yarney, Baffour Awuah, Beatrice Addai-Wiafe, The GBHS Study Team, Stephen J. Chanock, Andrew F. Olshan, Christine B. Ambrosone, David V. Conti, Elad Ziv, Olufunmilayo I. Olopade, Montserrat Garcia-Closas, Julie R. Palmer, Christopher A. Haiman, and Dezheng Huo

Subjects
Science
Abstract

GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.

Published
2021
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9. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

Daniel L. McCartney, Josine L. Min, Rebecca C. Richmond, Ake T. Lu, Maria K. Sobczyk, Gail Davies, Linda Broer, Xiuqing Guo, Ayoung Jeong, Jeesun Jung, Silva Kasela, Seyma Katrinli, Pei-Lun Kuo, Pamela R. Matias-Garcia, Pashupati P. Mishra, Marianne Nygaard, Teemu Palviainen, Amit Patki, Laura M. Raffield, Scott M. Ratliff, Tom G. Richardson, Oliver Robinson, Mette Soerensen, Dianjianyi Sun, Pei-Chien Tsai, Matthijs D. van der Zee, Rosie M. Walker, Xiaochuan Wang, Yunzhang Wang, Rui Xia, Zongli Xu, Jie Yao, Wei Zhao, Adolfo Correa, Eric Boerwinkle, Pierre-Antoine Dugué, Peter Durda, Hannah R. Elliott, Christian Gieger, The Genetics of DNA Methylation Consortium, Eco J. C. de Geus, Sarah E. Harris, Gibran Hemani, Medea Imboden, Mika Kähönen, Sharon L. R. Kardia, Jacob K. Kresovich, Shengxu Li, Kathryn L. Lunetta, Massimo Mangino, Dan Mason, Andrew M. McIntosh, Jonas Mengel-From, Ann Zenobia Moore, Joanne M. Murabito, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Miina Ollikainen, James S. Pankow, Nancy L. Pedersen, Annette Peters, Silvia Polidoro, David J. Porteous, Olli Raitakari, Stephen S. Rich, Dale P. Sandler, Elina Sillanpää, Alicia K. Smith, Melissa C. Southey, Konstantin Strauch, Hemant Tiwari, Toshiko Tanaka, Therese Tillin, Andre G. Uitterlinden, David J. Van Den Berg, Jenny van Dongen, James G. Wilson, John Wright, Idil Yet, Donna Arnett, Stefania Bandinelli, Jordana T. Bell, Alexandra M. Binder, Dorret I. Boomsma, Wei Chen, Kaare Christensen, Karen N. Conneely, Paul Elliott, Luigi Ferrucci, Myriam Fornage, Sara Hägg, Caroline Hayward, Marguerite Irvin, Jaakko Kaprio, Deborah A. Lawlor, Terho Lehtimäki, Falk W. Lohoff, Lili Milani, Roger L. Milne, Nicole Probst-Hensch, Alex P. Reiner, Beate Ritz, Jerome I. Rotter, Jennifer A. Smith, Jack A. Taylor, Joyce B. J. van Meurs, Paolo Vineis, Melanie Waldenberger, Ian J. Deary, Caroline L. Relton, Steve Horvath, and Riccardo E. Marioni

Subjects
DNA methylation, GWAS, Epigenetic clock, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Published
2021
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10. Reliability of DNA methylation measures using Illumina methylation BeadChip

Author

Zongli Xu and Jack A. Taylor

Subjects
ewas, methylation array, illumina, icc, Genetics, QH426-470
Abstract

Illumina BeadChips are widely utilized in epigenome-wide association studies (EWAS). Several studies have reported that many probes on these arrays have poor reliability. Here, we compare different pre-processing methods to improve intra-class correlation coefficients (ICC). We describe the characteristics of ICC across the genome, within and between studies, and across different array platforms. Using technical duplicates from 128 subjects, we find that with raw data only 22.5% of the CpGs on 450 K array have ‘acceptable’ ICCs (>0.5). Data preprocessing steps, such as background correction and dye bias correction, can reduce technical noise and improve the percentage to 38.5%. Similar to previous studies, we found that ICC is associated with CpG methylation level such that 83% of CpGs with intermediate methylation (0.10.9) have acceptable ICCs. ICC is also correlated with CpG methylation variance; after mutual adjustment for beta-value and variance, only variance remains correlated. Many CpGs with poor ICCs (

Published
2021
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11. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou

Subjects
Science
Abstract

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Published
2021
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12. Long-term ambient fine particulate matter and DNA methylation in inflammation pathways: results from the Sister Study

Author

Cuicui Wang, Katie M. O’Brien, Zongli Xu, Dale P. Sandler, Jack A. Taylor, and Clarice R. Weinberg

Subjects
long-term, pm2.5, methylation, quantile regression, Genetics, QH426-470
Abstract

Although underlying mechanisms of long-term exposure to air pollution and cardiovascular disease remain obscure, effects might partially act through changes in DNA methylation. We examined the associations between long-term ambient fine particulate matter (PM2.5) and methylation, considering both a global measure and methylation at several specific inflammation-related loci, in two random sub-cohorts selected from a nationwide prospective study of US women. In one sub-cohort we measured long interspersed nucleotide element (LINE-1); in the other, we measured methylation at three candidates CpG loci related to inflammatory pathways [tumour necrosis factor-alpha (TNF-α) and toll-like receptor-2 (TLR-2)]. Annual average contemporaneous ambient PM2.5 concentrations were estimated for the current residence. We used both classical least-squares and quantile regression models to estimate the long-term effects. The women in sub-cohorts 1 (n = 491) and 2 (n = 882) had mean ages of 55.8 and 56.7, respectively. Neither modelling approach showed an association between long-term PM2.5 and LINE-1 methylation or between PM2.5 and either of the two CpG sites in TLR-2. Using linear regression, there was an estimated change of −6.5% (95% confidence interval CI: −13.34%, 0.35%) in mean methylation of TNF-α per 5 µg/m3 increase in PM2.5. Quantile regression showed that the downward shift was mainly in the lower half of the distribution of DNA methylation. Long-term residence in regions with higher ambient PM2.5 may be associated with increased TNF-α through a reduction in methylation, particularly in the lower tail. Epigenetic markers and quantile regression might provide insight into mechanisms underlying the relationship between air pollution and cardiovascular disease.

Published
2020
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13. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R. Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H. M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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14. Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women

Author

Delores J. Grant, Ani Manichaikul, Anthony J. Alberg, Elisa V. Bandera, Jill Barnholtz‐Sloan, Melissa Bondy, Michele L. Cote, Ellen Funkhouser, Patricia G. Moorman, Lauren C. Peres, Edward S. Peters, Ann G. Schwartz, Paul D. Terry, Xin‐Qun Wang, Temitope O. Keku, Cathrine Hoyo, Andrew Berchuck, Dale P. Sandler, Jack A. Taylor, Katie M. O’Brien, Digna R. Velez Edwards, Todd L. Edwards, Alicia Beeghly‐Fadiel, Nicolas Wentzensen, Celeste Leigh Pearce, Anna H. Wu, Alice S. Whittemore, Valerie McGuire, Weiva Sieh, Joseph H. Rothstein, Francesmary Modugno, Roberta Ness, Kirsten Moysich, Mary Anne Rossing, Jennifer A. Doherty, Thomas A. Sellers, Jennifer B. Permuth‐Way, Alvaro N. Monteiro, Douglas A. Levine, Veronica Wendy Setiawan, Christopher A. Haiman, Loic LeMarchand, Lynne R. Wilkens, Beth Y. Karlan, Usha Menon, Susan Ramus, Simon Gayther, Aleksandra Gentry‐Maharaj, Kathryn L. Terry, Daniel W. Cramer, Ellen L. Goode, Melissa C. Larson, Scott H. Kaufmann, Rikki Cannioto, Kunle Odunsi, John L. Etter, Ruea‐Yea Huang, Marcus Q. Bernardini, Alicia A. Tone, Taymaa May, Marc T. Goodman, Pamela J. Thompson, Michael E. Carney, Shelley S. Tworoger, Elizabeth M. Poole, Diether Lambrechts, Ignace Vergote, Adriaan Vanderstichele, Els Van Nieuwenhuysen, Hoda Anton‐Culver, Argyrios Ziogas, James D. Brenton, Line Bjorge, Helga B. Salvensen, Lambertus A. Kiemeney, Leon F. A. G. Massuger, Tanja Pejovic, Amanda Bruegl, Melissa Moffitt, Linda Cook, Nhu D. Le, Angela Brooks‐Wilson, Linda E. Kelemen, Paul D.P. Pharoah, Honglin Song, Ian Campbell, Diana Eccles, Anna DeFazio, Catherine J. Kennedy, and Joellen M. Schildkraut

Subjects
African ancestry risk, genetic association, ovarian cancer, vitamin D pathway, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10−6, BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10−5, BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10−5, BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

Published
2019
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15. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Author

Leanne K. Küpers, Claire Monnereau, Gemma C. Sharp, Paul Yousefi, Lucas A. Salas, Akram Ghantous, Christian M. Page, Sarah E. Reese, Allen J. Wilcox, Darina Czamara, Anne P. Starling, Alexei Novoloaca, Samantha Lent, Ritu Roy, Cathrine Hoyo, Carrie V. Breton, Catherine Allard, Allan C. Just, Kelly M. Bakulski, John W. Holloway, Todd M. Everson, Cheng-Jian Xu, Rae-Chi Huang, Diana A. van der Plaat, Matthias Wielscher, Simon Kebede Merid, Vilhelmina Ullemar, Faisal I. Rezwan, Jari Lahti, Jenny van Dongen, Sabine A. S. Langie, Tom G. Richardson, Maria C. Magnus, Ellen A. Nohr, Zongli Xu, Liesbeth Duijts, Shanshan Zhao, Weiming Zhang, Michelle Plusquin, Dawn L. DeMeo, Olivia Solomon, Joosje H. Heimovaara, Dereje D. Jima, Lu Gao, Mariona Bustamante, Patrice Perron, Robert O. Wright, Irva Hertz-Picciotto, Hongmei Zhang, Margaret R. Karagas, Ulrike Gehring, Carmen J. Marsit, Lawrence J. Beilin, Judith M. Vonk, Marjo-Riitta Jarvelin, Anna Bergström, Anne K. Örtqvist, Susan Ewart, Pia M. Villa, Sophie E. Moore, Gonneke Willemsen, Arnout R. L. Standaert, Siri E. Håberg, Thorkild I. A. Sørensen, Jack A. Taylor, Katri Räikkönen, Ivana V. Yang, Katerina Kechris, Tim S. Nawrot, Matt J. Silver, Yun Yun Gong, Lorenzo Richiardi, Manolis Kogevinas, Augusto A. Litonjua, Brenda Eskenazi, Karen Huen, Hamdi Mbarek, Rachel L. Maguire, Terence Dwyer, Martine Vrijheid, Luigi Bouchard, Andrea A. Baccarelli, Lisa A. Croen, Wilfried Karmaus, Denise Anderson, Maaike de Vries, Sylvain Sebert, Juha Kere, Robert Karlsson, Syed Hasan Arshad, Esa Hämäläinen, Michael N. Routledge, Dorret I. Boomsma, Andrew P. Feinberg, Craig J. Newschaffer, Eva Govarts, Matthieu Moisse, M. Daniele Fallin, Erik Melén, Andrew M. Prentice, Eero Kajantie, Catarina Almqvist, Emily Oken, Dana Dabelea, H. Marike Boezen, Phillip E. Melton, Rosalind J. Wright, Gerard H. Koppelman, Letizia Trevisi, Marie-France Hivert, Jordi Sunyer, Monica C. Munthe-Kaas, Susan K. Murphy, Eva Corpeleijn, Joseph Wiemels, Nina Holland, Zdenko Herceg, Elisabeth B. Binder, George Davey Smith, Vincent W. V. Jaddoe, Rolv T. Lie, Wenche Nystad, Stephanie J. London, Debbie A. Lawlor, Caroline L. Relton, Harold Snieder, and Janine F. Felix

Subjects
Science
Abstract

Birthweight has been found to associate with later-life health outcomes. Here the authors perform a meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, identifying differentially methylated CpGs in neonatal blood that associate with birthweight.

Published
2019
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16. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author

Manuel A. Ferreira, Eric R. Gamazon, Fares Al-Ejeh, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Ella Asseryanis, Jacopo Azzollini, Judith Balmaña, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Ake Borg, Hiltrud Brauch, Hermann Brenner, Annegien Broeks, Barbara Burwinkel, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Ian Campbell, Federico Canzian, Jonathan Carter, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Miguel de la Hoya, Joe Dennis, Peter Devilee, Orland Diez, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Bent Ejlertsen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Eitan Friedman, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Wei He, Jane Heyworth, Frans B. L. Hogervorst, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Peter J. Hulick, Keith Humphreys, Evgeny N. Imyanitov, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Vijai Joseph, Beth Y. Karlan, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Michael E. Jones, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Sara Lindström, Jirong Long, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn C. Nielsen, Liene Nikitina-Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Ana Osorio, Janos Papp, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Paolo Peterlongo, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Bruce Poppe, Nadege Presneau, Paolo Radice, Johanna Rantala, Gad Rennert, Harvey A. Risch, Emmanouil Saloustros, Kristin Sanden, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F. Singer, Penny Soucy, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Anthony J. Swerdlow, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Mary Beth Terry, Alex Teulé, Mads Thomassen, Kathrin Thöne, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Thérèse Truong, Nadine Tung, Celine M. Vachon, Christi J. van Asperen, Ans M. W. van den Ouweland, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Qin Wang, Barbara Wappenschmidt, Jeffrey N. Weitzel, Camilla Wendt, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Peter Kraft, Antonis C. Antoniou, Wei Zheng, Douglas F. Easton, Roger L. Milne, Jonathan Beesley, and Georgia Chenevix-Trench

Subjects
Science
Abstract

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

Published
2019
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17. A comparison of DNA methylation in newborn blood samples from infants with and without orofacial clefts

Author

Zongli Xu, Rolv T. Lie, Allen J. Wilcox, Ola Didrik Saugstad, and Jack A. Taylor

Subjects
DNA methylation, Cleft lip, Cleft palate, Blood, Newborns, Medicine, Genetics, QH426-470
Abstract

Abstract Background Isolated orofacial clefts are among the most common congenital birth defects. Although the underlying biological mechanisms remain largely unknown, clefts are thought to be complex disorders influenced by genetic, environmental, and potentially epigenetic factors. Methods In blood samples from 2- to 3-day-old infants (n = 747) collected in a nationwide population-based study of orofacial clefts in Norway, we measured DNA methylation profiles for more than 450,000 CpGs and then conducted epigenome-wide association analyses (EWAS). We tested methylation profile difference at each CpG between controls (n = 436) and each of the cleft subtypes (92 cleft lip only, CLO; 84 cleft palate only, CPO; 132 cleft lip and palate, CLP). We also compared controls to various combinations of case groups and compared case subtypes to each other. Finally, using the EWAS results, we searched for larger differentially methylated regions (DMRs) associated with orofacial clefts. Results In EWAS comparing controls to individual cleft subtypes, we found no significant associations at a Bonferroni P value threshold of 10−7. After pooling case groups, we found two significantly differentially methylated CpGs: cg09696939 near gene BICC1 is associated with CLO+CLP (P = 9.58 × 10−8); cg26985354 in gene CLASRP is associated with CPO+CLP (P = 7.38 × 10−8). In DMR analysis, we identified a total of 56 significant regions when comparing controls to individual cleft subtypes (10 for CLO, 6 for CPO, 41 for CLP). Only one DMR is shared among the three cleft groups. In combined case group analysis, we found 26 DMRs for CLP+CLO, 31 for CLP+CPO, and 37 when all subtypes are combined. Finally, in case-case comparisons of subtypes, we identified 10 DMRs when comparing CLP to CPO, 9 in CLP compared to CLO, and 13 in CLP compared to CPO. Conclusions We identified two individual CpGs and multiple DMRs that differ between controls and cleft case subtypes. Although we find some evidence for the possible role of DNA methylation in etiology of orofacial clefts, our study does not support previous reports of widespread differences in blood DNA methylation between babies with and without facial clefts.

Published
2019
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18. Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Author

Sophia Harlid, Zongli Xu, Erin Kirk, Lauren E. Wilson, Melissa A. Troester, and Jack A. Taylor

Subjects
hormone therapy, normal breast tissue, dna methylation, epigenetics, epigenome wide association, Genetics, QH426-470
Abstract

Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q

Published
2019
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19. Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Published
2019
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20. Vitamin D, DNA methylation, and breast cancer

Author

Katie M. O’Brien, Dale P. Sandler, Zongli Xu, H. Karimi Kinyamu, Jack A. Taylor, and Clarice R. Weinberg

Subjects
Breast cancer, Vitamin D, 25-Hydroxyvitamin D, DNA methylation, Epigenome-wide association study, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Vitamin D has anticarcinogenic and immune-related properties and may protect against some diseases, including breast cancer. Vitamin D affects gene transcription and may influence DNA methylation. Methods We studied the relationships between serum vitamin D, DNA methylation, and breast cancer using a case-cohort sample (1070 cases, 1277 in subcohort) of non-Hispanic white women. For our primary analysis, we used robust linear regression to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and methylation within a random sample of the cohort (“subcohort”). We focused on 198 CpGs in or near seven vitamin D-related genes. For these 198 candidate CpG loci, we also examined how multiplicative interactions between methylation and 25(OH)D were associated with breast cancer risk. This was done using Cox proportional hazards models and the full case-cohort sample. We additionally conducted an exploratory epigenome-wide association study (EWAS) of the association between 25(OH)D and DNA methylation in the subcohort. Results Of the CpGs in vitamin D-related genes, cg21201924 (RXRA) had the lowest p value for association with 25(OH)D (p = 0.0004). Twenty-two other candidate CpGs were associated with 25(OH)D (p

Published
2018
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21. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou

Subjects
Science
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4

Published
2021
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22. Air pollution, particulate matter composition and methylation-based biologic age

Author

Alexandra J. White, Jacob K. Kresovich, Joshua P. Keller, Zongli Xu, Joel D. Kaufman, Clarice R. Weinberg, Jack A. Taylor, and Dale P. Sandler

Subjects
Environmental sciences, GE1-350
Abstract

Background: Epigenetic age, as defined by DNA methylation, may be influenced by air pollution exposure. Objective: To evaluate the relationship between NO2, particulate matter (PM), PM components and accelerated epigenetic age. Methods: In a sample of non-Hispanic white women living in the contiguous U.S. (n = 2747), we estimated residential exposure to PM2.5, PM10 and NO2 using a model incorporating land-use regression and kriging. Predictive k-means was used to assign participants to clusters representing different PM2.5 component profiles. We measured DNA methylation (DNAm) in blood using the Illumina's Infinium HumanMethylation450 BeadChip and calculated DNAm age using the Hannum, Horvath and Levine epigenetic clocks. Age acceleration was defined based on residuals after regressing DNAm age on chronological age. We estimated associations between interquartile range (IQR) increases in pollutants and age acceleration using linear regression. For PM2.5, we stratified by cluster membership. We examined epigenome-wide associations using robust linear regression models corrected with false discovery rate q-values. Results: NO2 was inversely associated with age acceleration using the Hannum clock (β = −0.24, 95% CI: −0.47, −0.02). No associations were observed for PM10. For PM2.5, the association with age acceleration varied by PM2.5 component cluster. For example, with the Levine clock, an IQR increase in PM2.5 was associated with an over 6-year age acceleration in a cluster that has relatively high fractions of crustal elements relative to overall PM2.5 (β = 6.57, 95% CI: 2.68, 10.47), and an almost 2-year acceleration in a cluster characterized by relatively low sulfur fractions (β = 1.88, 95% CI: 0.51, 3.25). In a cluster distinguished by lower relative nitrate concentrations, PM2.5 was inversely associated with age acceleration (β = −1.33, 95% CI: −2.43, −0.23). Across the epigenome, NO2 was associated with methylation at 2 CpG sites. Conclusion: Air pollution was associated with epigenetic age, a marker of mortality and disease risk, among certain PM2.5 component profiles. Keywords: Breast cancer, Air pollution, Particulate matter, Clustering, Mixtures

Published
2019
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23. Genome-Wide Association Study of Serum 25-Hydroxyvitamin D in US Women

Author

Katie M. O'Brien, Dale P. Sandler, Min Shi, Quaker E. Harmon, Jack A. Taylor, and Clarice R. Weinberg

Subjects
25-dihydroxy vitamin D, genome-wide association study, single nucleotide polymorphism, vitamin D binding protein, CYP2R1, Genetics, QH426-470
Abstract

Genetic factors likely influence individuals' concentrations of 25-hydroxyvitamin D [25(OH)D], a biomarker of vitamin D exposure previously linked to reduced risk of several chronic diseases. We conducted a genome-wide association study of serum 25(OH)D (assessed using liquid chromatography-tandem mass spectrometry) and 386,449 single nucleotide polymorphisms (SNPs). Our sample consisted of 1,829 participants randomly selected from the Sister Study, a cohort of women who had a sister with breast cancer but had never had breast cancer themselves. 19,741 SNPs were associated with 25(OH)D (p < 0.05). We re-assessed these hits in an independent sample of 1,534 participants who later developed breast cancer. After pooling, 32 SNPs had genome-wide significant associations (p < 5 × 10−8). These were located in or near GC, the vitamin D binding protein, or CYP2R1, a cytochrome P450 enzyme that hydroxylates vitamin D to form 25(OH)D. The top hit was rs4588, a missense GC polymorphism associated with a 3.5 ng/mL decrease in 25(OH)D per copy of the minor allele (95% confidence interval [CI]: −4.1, −3.0; p = 4.5 × 10−38). The strongest SNP near CYP2R1 was rs12794714, a synonymous variant (p = 3.8 × 10−12; β = 1.8 ng/mL decrease in 25(OH)D per minor allele [CI: −2.2, −1.3]). Serum 25(OH)D concentrations from samples collected from some participants 3–10 years after baseline (811 cases, 780 non-cases) were also strongly associated with both loci. These findings augment our understanding of genetic influences on 25(OH)D and the possible role of vitamin D binding proteins and cytochrome P450 enzymes in determining measured levels. These results may help to identify individuals genetically predisposed to vitamin D insufficiency.

Published
2018
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24. Assessing Candidate Gene nsSNPs for Phenotypic Differences in Double-Strand Break Repair Using Radiation-Induced γH2A.X Foci

Author

Christina A. Markunas, David M. Umbach, Zongli Xu, and Jack A. Taylor

Subjects
Medicine
Abstract

Nonsynonymous SNPs (nsSNPs) in DNA repair genes may be important determinants of DNA damage and cancer risk. We applied a set of screening criteria to a large number of nsSNPs and selected a subset of SNPs that were likely candidates for phenotypic effects on DNA double-strand break repair (DSBR). In order to induce and follow DSBR, we exposed panels of cell lines to gamma irradiation and followed the formation and disappearance of γH2A.X foci over time. All panels of cell lines showed significant increases in number, intensity, and area of foci at both the 1-hour and 3-hour time points. Twenty four hours following exposure, the number of foci returned to preexposure levels in all cell lines, whereas the size and intensity of foci remained significantly elevated. We saw no significant difference in γH2A.X foci between controls and any of the panels of cell lines representing the different nsSNPs.

Published
2008
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26. Methylation-Based Biological Age and Hypertension Prevalence and Incidence

Author

Jacob K. Kresovich, Dale P. Sandler, and Jack A. Taylor

Subjects
Internal Medicine
Abstract

Background: Hypertension is common in older individuals and is a major risk factor for cardiovascular disease. Blood DNA methylation profiles have been used to derive metrics of biological age that capture age-related physiological change, disease risk, and mortality. The relationships between hypertension and DNA methylation-based biological age metrics have yet to be carefully described. Methods: Among 4419 women enrolled in the prospective Sister Study cohort, DNA methylation data generated from whole blood samples collected at baseline were used to calculate 3 biological age metrics (PhenoAgeAccel, GrimAgeAccel, DunedinPACE). Women were classified as hypertensive at baseline if they had high blood pressure (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) or reported current use of antihypertensive medication. New incident cases of hypertension during follow-up were identified via self-report on annual health questionnaires. Results: All 3 DNA methylation metrics of biological age were positively associated with prevalent hypertension at baseline (per 1-SD increase; PhenoAgeAccel, adjusted odds ratio, 1.16 [95% CI, 1.05–1.28]; GrimAgeAccel, adjusted odds ratio, 1.28 [95% CI, 1.14–1.45]; DunedinPACE, adjusted odds ratio, 1.16 [95% CI, 1.03–1.30]). Among 2610 women who were normotensive at baseline, women with higher biological age were more likely to be diagnosed with incident hypertension (per 1-SD increase; PhenoAgeAccel, adjusted hazard ratio, 1.09 [95% CI, 0.97–1.23]; GrimAgeAccel, adjusted hazard ratio, 1.16 [95% CI, 0.99–1.36]; DunedinPACE, adjusted hazard ratio, 1.16 [95% CI, 1.01–1.33]). Conclusions: Methylation-based biological age metrics increase before a hypertension diagnosis and appear to remain elevated in the years after clinical diagnosis and treatment.

Published
2023
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27. Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2

Author

Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Susan Holtegaard, Huaizhi Huang, Carolyn A. Dunn, Lauren R. Teras, Alpa V. Patel, James V. Lacey, Susan L. Neuhausen, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn J. Ruddy, Janet E. Olson, Esther M. John, Allison W. Kurian, Dale P. Sandler, Katie M. O'Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary Zirpoli, David E. Goldgar, Julie R. Palmer, Susan M. Domchek, Jeffrey N. Weitzel, Katherine L. Nathanson, Peter Kraft, and Fergus J. Couch

Subjects
Cancer Research, Oncology
Abstract

PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Published
2023
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28. Beadchip technology to detect DNA methylation in mouse faithfully recapitulates whole-genome bisulfite sequencing

Author

Elizabeth M Martin, Sara A Grimm, Zongli Xu, Jack A Taylor, and Paul A Wade

Subjects
Cancer Research, Genetics
Abstract

Aim: To facilitate wide-scale implementation of Illumina Mouse Methylation BeadChip (MMB) technology, array-based measurement of cytosine methylation was compared with the gold-standard assessment of DNA methylation by whole-genome bisulfite sequencing (WGBS). Methods: DNA methylation across two mouse strains (C57B6 and C3H) and both sexes was assessed using the MMB and compared with previously existing deep-coverage WGBS of mice of the same strain and sex. Results & conclusion: The findings demonstrated that 93.3–99.2% of sites had similar measurements of methylation across technologies and that differentially methylated cytosines and regions identified by each technology overlap and enrich for similar biological functions, suggesting that the MMB faithfully recapitulates the findings of WGBS.

Published
2023
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30. Data from Systemic Levels of Estrogens and PGE2 Synthesis in Relation to Postmenopausal Breast Cancer Risk

Author

Dale P. Sandler, Jack A. Taylor, Wonsuk Yoo, Jeff Campbell, and Sangmi Kim

Abstract

Background:Prostaglandin E2 (PGE2) induces aromatase expression in adipose tissue, leading to increased estrogen production that may promote the development and progression of breast cancer. However, few studies have simultaneously investigated systemic levels of PGE2 and estrogen in relation to postmenopausal breast cancer risk.Methods:Here, we determined urinary estrogen metabolites (EM) using mass spectrometry in a case–cohort study (295 incident breast cancer cases and 294 subcohort members), and using linear regression estimated the effect of urinary levels of a major PGE2 metabolite (PGE-M) on EMs. HRs for the risk of developing breast cancer in relation to PGE-M and EMs were compared between Cox regression models with and without mutual adjustment.Results:PGE-M was a significant predictor of estrone (E1), but not estradiol (E2) levels in multivariable analysis. Elevated E2 levels were associated with an increased risk of developing breast cancer [HRQ5vs.Q1, 1.54; 95% confidence interval (CI), 1.01–2.35], and this association remained unchanged after adjustment for PGE-M (HRQ5vs.Q1, 1.52; 95% CI, 0.99–2.33). Similarly, elevated levels of PGE-M were associated with increased risk of developing breast cancer (HRQ4vs.Q1, 2.01; 95% CI, 1.01–4.29), and this association was only nominally changed after consideration of E1 or E2 levels.Conclusions:Urinary levels of PGE-M and estrogens were independently associated with future risk of developing breast cancer among these postmenopausal women.Impact:Increased breast cancer risk associated with PGE-M might not be fully explained by the estrogens–breast cancer association alone but also by additional effects related to inflammation. Cancer Epidemiol Biomarkers Prev; 26(3); 383–8. ©2016 AACR.

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2023
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32. Supplementary Tables 1-3 from A Genome-Wide Gene-Based Gene–Environment Interaction Study of Breast Cancer in More than 90,000 Women

Author

Sara Lindström, Jenny Chang-Claude, Peter Kraft, Li Hsu, Roger L. Milne, Douglas F. Easton, Håkan Olsson, Sophia Wang, James V. Lacey, Nick Orr, Anthony J. Swerdlow, Jack A. Taylor, Dale P. Sandler, Alicja Wolk, Kamila Czene, Per Hall, Anthony Howell, D. Gareth Evans, Rose Yang, Thomas Ahearn, Jonine Figueroa, Montserrat García-Closas, Heather Eliassen, Rulla Tamimi, Cheng Peng, Michael I. Love, Melissa A. Troester, Jirong Long, Wei Zheng, Mark S. Goldberg, Jacques Simard, Stacey Winham, Christopher Scott, Gertraud Maskarinec, Christopher A. Haiman, Graham G. Giles, Heiko Becher, Audrey Jung, Veli-Matti Kosma, Arto Mannermaa, Sabine Behrens, Wing-Yee Lo, Reiner Hoppe, Volker Arndt, Hermann Brenner, Rudolf Kaaks, Federico Canzian, James M. Hodge, Lauren R. Teras, Thérèse Truong, Pascal Guénel, Kristan Aronson, Rachel A. Murphy, Rana Shibli, Gad Rennert, Jennifer Stone, Laura E. Beane Freeman, Stella Koutros, Melissa C. Southey, John L. Hopper, Paul D.P. Pharoah, Kyriaki Michailidou, Qin Wang, Michael Lush, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Yu-Ru Su, Pooja Middha Kapoor, Hongjie Chen, and Xiaoliang Wang

Abstract

Supplementary Table 1. Sample Size of each participated study, by case-control status and genotype platform. Supplementary Table 2. Association between fourteen environmental factors and the risk of breast cancer. Supplementary Table 3. Interactions between genes and fourteen environmental factors.

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2023
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33. Data from A Genome-Wide Gene-Based Gene–Environment Interaction Study of Breast Cancer in More than 90,000 Women

Author

Sara Lindström, Jenny Chang-Claude, Peter Kraft, Li Hsu, Roger L. Milne, Douglas F. Easton, Håkan Olsson, Sophia Wang, James V. Lacey, Nick Orr, Anthony J. Swerdlow, Jack A. Taylor, Dale P. Sandler, Alicja Wolk, Kamila Czene, Per Hall, Anthony Howell, D. Gareth Evans, Rose Yang, Thomas Ahearn, Jonine Figueroa, Montserrat García-Closas, Heather Eliassen, Rulla Tamimi, Cheng Peng, Michael I. Love, Melissa A. Troester, Jirong Long, Wei Zheng, Mark S. Goldberg, Jacques Simard, Stacey Winham, Christopher Scott, Gertraud Maskarinec, Christopher A. Haiman, Graham G. Giles, Heiko Becher, Audrey Jung, Veli-Matti Kosma, Arto Mannermaa, Sabine Behrens, Wing-Yee Lo, Reiner Hoppe, Volker Arndt, Hermann Brenner, Rudolf Kaaks, Federico Canzian, James M. Hodge, Lauren R. Teras, Thérèse Truong, Pascal Guénel, Kristan Aronson, Rachel A. Murphy, Rana Shibli, Gad Rennert, Jennifer Stone, Laura E. Beane Freeman, Stella Koutros, Melissa C. Southey, John L. Hopper, Paul D.P. Pharoah, Kyriaki Michailidou, Qin Wang, Michael Lush, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Yu-Ru Su, Pooja Middha Kapoor, Hongjie Chen, and Xiaoliang Wang

Abstract

Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this.We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P < 0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test.After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE = 4.44 × 10−6).In this transcriptome-informed genome-wide gene–environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk.Our study suggests a limited role of gene–environment interactions in breast cancer risk.

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2023
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34. Supplementary Information from A Genome-Wide Gene-Based Gene–Environment Interaction Study of Breast Cancer in More than 90,000 Women

Author

Sara Lindström, Jenny Chang-Claude, Peter Kraft, Li Hsu, Roger L. Milne, Douglas F. Easton, Håkan Olsson, Sophia Wang, James V. Lacey, Nick Orr, Anthony J. Swerdlow, Jack A. Taylor, Dale P. Sandler, Alicja Wolk, Kamila Czene, Per Hall, Anthony Howell, D. Gareth Evans, Rose Yang, Thomas Ahearn, Jonine Figueroa, Montserrat García-Closas, Heather Eliassen, Rulla Tamimi, Cheng Peng, Michael I. Love, Melissa A. Troester, Jirong Long, Wei Zheng, Mark S. Goldberg, Jacques Simard, Stacey Winham, Christopher Scott, Gertraud Maskarinec, Christopher A. Haiman, Graham G. Giles, Heiko Becher, Audrey Jung, Veli-Matti Kosma, Arto Mannermaa, Sabine Behrens, Wing-Yee Lo, Reiner Hoppe, Volker Arndt, Hermann Brenner, Rudolf Kaaks, Federico Canzian, James M. Hodge, Lauren R. Teras, Thérèse Truong, Pascal Guénel, Kristan Aronson, Rachel A. Murphy, Rana Shibli, Gad Rennert, Jennifer Stone, Laura E. Beane Freeman, Stella Koutros, Melissa C. Southey, John L. Hopper, Paul D.P. Pharoah, Kyriaki Michailidou, Qin Wang, Michael Lush, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Yu-Ru Su, Pooja Middha Kapoor, Hongjie Chen, and Xiaoliang Wang

Abstract

Funding and acknowledgements.

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2023
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35. Supplementary Figure 1 from A Genome-Wide Gene-Based Gene–Environment Interaction Study of Breast Cancer in More than 90,000 Women

Author

Sara Lindström, Jenny Chang-Claude, Peter Kraft, Li Hsu, Roger L. Milne, Douglas F. Easton, Håkan Olsson, Sophia Wang, James V. Lacey, Nick Orr, Anthony J. Swerdlow, Jack A. Taylor, Dale P. Sandler, Alicja Wolk, Kamila Czene, Per Hall, Anthony Howell, D. Gareth Evans, Rose Yang, Thomas Ahearn, Jonine Figueroa, Montserrat García-Closas, Heather Eliassen, Rulla Tamimi, Cheng Peng, Michael I. Love, Melissa A. Troester, Jirong Long, Wei Zheng, Mark S. Goldberg, Jacques Simard, Stacey Winham, Christopher Scott, Gertraud Maskarinec, Christopher A. Haiman, Graham G. Giles, Heiko Becher, Audrey Jung, Veli-Matti Kosma, Arto Mannermaa, Sabine Behrens, Wing-Yee Lo, Reiner Hoppe, Volker Arndt, Hermann Brenner, Rudolf Kaaks, Federico Canzian, James M. Hodge, Lauren R. Teras, Thérèse Truong, Pascal Guénel, Kristan Aronson, Rachel A. Murphy, Rana Shibli, Gad Rennert, Jennifer Stone, Laura E. Beane Freeman, Stella Koutros, Melissa C. Southey, John L. Hopper, Paul D.P. Pharoah, Kyriaki Michailidou, Qin Wang, Michael Lush, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Yu-Ru Su, Pooja Middha Kapoor, Hongjie Chen, and Xiaoliang Wang

Abstract

Quantile-Quantile plot (Q-Q plot) of the aMiSTi p-values for each set of the GxE interactions.

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2023
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36. Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research

Author

Jack Carson Taylor, Hilary W. Heuer, Annie L. Clark, Amy B. Wise, Masood Manoochehri, Leah Forsberg, Carly Mester, Meghana Rao, Daniell Brushaber, Joel Kramer, Ariane E. Welch, John Kornak, Walter Kremers, Brian Appleby, Bradford C. Dickerson, Kimiko Domoto‐Reilly, Julie A. Fields, Nupur Ghoshal, Neill Graff‐Radford, Murray Grossman, Matthew GH Hall, Edward D. Huey, David Irwin, Maria I. Lapid, Irene Litvan, Ian R. Mackenzie, Joseph C. Masdeu, Mario F. Mendez, Naomi Nevler, Chiadi U. Onyike, Belen Pascual, Peter Pressman, Katherine P. Rankin, Buddhika Ratnasiri, Julio C. Rojas, Maria Carmela Tartaglia, Bonnie Wong, Maria Luisa Gorno‐Tempini, Bradley F. Boeve, Howard J. Rosen, Adam L. Boxer, and Adam M. Staffaroni

Subjects
cognition, Aging, neuropsychology, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, smartphone, Brain Disorders, Psychiatry and Mental health, Frontotemporal Dementia (FTD), Rare Diseases, frontotemporal lobar degeneration, Clinical Research, Behavioral and Social Science, Neurological, Acquired Cognitive Impairment, Genetics, primary progressive aphasia, Dementia, Neurology (clinical), adherence, digital technology
Abstract

IntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD=0 [N=101]; prodromal: 0.5 [N=49]; symptomatic ≥1 [N=51]; not measured [N=13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research.HighlightsThe ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses.

Published
2023

37. Data from Single-Nucleotide Polymorphisms in Vitamin D–Related Genes May Modify Vitamin D–Breast Cancer Associations

Author

Clarice R. Weinberg, Jack A. Taylor, H. Karimi Kinyamu, Dale P. Sandler, and Katie M. O'Brien

Abstract

Background: We previously observed that high serum 25-hydroxyvitamin D (25(OH)D; >38.0 ng/mL) was inversely associated with breast cancer. Here, we examined effect modification by SNPs in vitamin D–related genes.Methods: The Sister Study enrolled 50,884 U.S. women who had a sister with breast cancer, but who had never had breast cancer themselves. Using a case–cohort design, we compared 1,524 women who developed breast cancer within 5 years to 1,810 randomly selected participants. We estimated ratios of HRs (RHRs) for the 25(OH)D–breast cancer association per copy of the minor allele using Cox proportional hazards models. We considered 82 SNPs in 7 vitamin D–related genes (CYP24A1, CYP27B1, CYP2R1, GC, DHCR7/NADSYN1, RXRA, and VDR). We also tested gene-based interactions with 25(OH)D.Results: The SNP with the smallest interaction P value was rs4328262 in VDR (P = 0.0008); the 25(OH)D HR was 0.92 [95% confidence interval (CI), 0.68–1.24] among those homozygous for the common allele, and the minor allele was estimated to decrease the HR by 33% per copy (RHR = 0.67; 95% CI, 0.53–0.85). Five other VDR SNPs showed evidence of interaction at P < 0.05, as did one SNP in CYP2R1 and one in RXRA. As a group, the 82 SNPs showed evidence of multiplicative interaction with 25(OH)D (P = 0.04). In gene-based tests, only VDR showed strong evidence of interaction (P = 0.04).Conclusions: SNPs in vitamin D–related genes may modify the association between serum 25(OH)D and breast cancer.Impact: This work strengthens the evidence for protective effects of vitamin D. Cancer Epidemiol Biomarkers Prev; 26(12); 1761–71. ©2017 AACR.

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2023
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38. Data from The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author

Douglas F. Easton, Jacques Simard, Stephen J. Chanock, Georgia Chenevix-Trench, Paul D.P. Pharoah, Antonis C. Antoniou, Daniela Seminara, Elizabeth Gillanders, Michael F. Seldin, Rosalind A. Eeles, Ulrike Peters, Ali Amin Al Olama, Jonathan Marchini, Rayjean J. Hung, Laura Ottini, Rita Schmutzler, Mads Thomassen, Kenneth Offit, Sue K. Park, John K. Field, Jack A. Taylor, Christopher K. Edlund, Tameka Shelford, Stephanie L. Schmit, Sylvie Laboissiere, Andrew Berchuck, Sune F. Nielsen, Marc T. Goodman, Deborah J. Thompson, Yongyong Shi, Hongbing Shen, Tracy A. O'Mara, Marjorie Riggan, Paul Brennan, Linda E. Kelemen, Sara Benlloch, Catherine M. Phelan, James D. McKay, Marcia Adams, Sara Lindström, Liesel FitzGerald, Peter Kraft, Zsofia Kote-Jarai, Katja Butterbach, Julie M. Cunningham, Judith Manz, Penny Soucy, Karoline Kuchenbaecker, Andrew Lee, Lesley McGuffog, Hua Ling, Belynda D. Hicks, Irene Brüske-Hohlfeld, Melanie Waldenberger, Angela Risch, Heike Bickeböller, David V. Conti, Graham G. Giles, Judith L. Forman, Fergus J. Couch, David E. Goldgar, Stephen Demetriades, Stefanie Nelson, David J. Van Den Berg, François Bacot, Daniel Vincent, Daniel Tessier, Craig Luccarini, Ahsan Kamal, Christopher A. Haiman, Charlisse Caga-Anan, Stig E. Bojesen, Dennis J. Hazelett, Gerhard A. Coetzee, Elizabeth Pugh, Jane Romm, Xiangjun Xiao, Yafang Li, Amanda B. Spurdle, Kimberly Doheny, Laura Fachal, Kyriaki Michailidou, Alison M. Dunning, Stephen B. Gruber, Thomas A. Sellers, David J. Hunter, Graham Casey, Simon A. Gayther, Fredrick R. Schumacher, Jinyoung Byun, Zhaoming Wang, Joe Dennis, and Christopher I. Amos

Abstract

Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits.Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background.Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis.Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures.Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126–35. ©2016 AACR.

Published
2023
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39. Supplementary Tables from Single-Nucleotide Polymorphisms in Vitamin D–Related Genes May Modify Vitamin D–Breast Cancer Associations

Author

Clarice R. Weinberg, Jack A. Taylor, H. Karimi Kinyamu, Dale P. Sandler, and Katie M. O'Brien

Abstract

Supplementary Table 1. Between SNP correlations (r2) for VDR SNPs among sub-cohort sample from the Sister Study (n=1829); Supplementary Table 2. Joint effects of 25(OH)D and single nucleotide polymorphisms (SNPs) in vitamin D metabolism genes on the 5-year risk of post-menopausal breast cancer: Ratio of hazard ratios and 95% confidence intervals; Supplementary Table 3. Joint effects of 25(OH)D and single nucleotide polymorphisms (SNPs) in vitamin D metabolism genes on the 5-year risk of breast cancer according to first-degree family history: Minor allele frequencies (MAFs), Ratio of hazard ratios (RHR), 95% confidence intervals (95% CI), and interaction p-values (top 12 SNPs only); Supplementary Table 4. Top hits for joint effects of 25(OH)D and single nucleotide polymorphisms (SNPs) in other vitamin D-related genes on the 5-year risk of breast cancer; Supplementary Table 5. Gene-environment set association tests (GESAT) for 25(OH)D and other vitamin D-related genes on the 5-year risk of breast cancer

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2023
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40. Data from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Author

Montserrat Garcia-Closas, Sung Shim Lani Park, Cecilia Arici, Marcello Campagna, Angela Carta, Stefano Porru, Peter Rudnai, Rajiv Kumar, Kvetoslava Koppova, Eugen Gurzau, Alessandra Allione, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Paolo Vineis, Yu-Tang Gao, Yong-Bing Xiang, Victoria K. Cortessis, Manuela Gago-Dominguez, Amit D. Joshi, Román Corral, Faye Elliot, Jennifer H. Barrett, Ananya Choudhury, Sei Chung Sak, D. Timothy Bishop, Heather H. Nelson, Angeline S. Andrew, Margaret R. Karagas, Xifeng Wu, Stephen Chanock, Nuria Malats, Debra Silverman, Manolis Kogevinas, Nathaniel Rothman, Gunnar Steineck, Zuo-Feng Zhang, Donatella Placidi, Jack A. Taylor, Simone Benhamou, Tony Fletcher, Giuseppe Matullo, Jian-Min Yuan, Anne E. Kiltie, Karl T. Kelsey, Jonine D. Figueroa, Jie Lin, and Mariana C. Stern

Abstract

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01–1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01–1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00–1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. [Cancer Res 2009;69(17):6857–64]

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2023
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41. Supplementary Tables 1-8 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Author

Montserrat Garcia-Closas, Sung Shim Lani Park, Cecilia Arici, Marcello Campagna, Angela Carta, Stefano Porru, Peter Rudnai, Rajiv Kumar, Kvetoslava Koppova, Eugen Gurzau, Alessandra Allione, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Paolo Vineis, Yu-Tang Gao, Yong-Bing Xiang, Victoria K. Cortessis, Manuela Gago-Dominguez, Amit D. Joshi, Román Corral, Faye Elliot, Jennifer H. Barrett, Ananya Choudhury, Sei Chung Sak, D. Timothy Bishop, Heather H. Nelson, Angeline S. Andrew, Margaret R. Karagas, Xifeng Wu, Stephen Chanock, Nuria Malats, Debra Silverman, Manolis Kogevinas, Nathaniel Rothman, Gunnar Steineck, Zuo-Feng Zhang, Donatella Placidi, Jack A. Taylor, Simone Benhamou, Tony Fletcher, Giuseppe Matullo, Jian-Min Yuan, Anne E. Kiltie, Karl T. Kelsey, Jonine D. Figueroa, Jie Lin, and Mariana C. Stern

Abstract

Supplementary Tables 1-8 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

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2023
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42. Supplementary Figure Legend from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Author

Montserrat Garcia-Closas, Sung Shim Lani Park, Cecilia Arici, Marcello Campagna, Angela Carta, Stefano Porru, Peter Rudnai, Rajiv Kumar, Kvetoslava Koppova, Eugen Gurzau, Alessandra Allione, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Paolo Vineis, Yu-Tang Gao, Yong-Bing Xiang, Victoria K. Cortessis, Manuela Gago-Dominguez, Amit D. Joshi, Román Corral, Faye Elliot, Jennifer H. Barrett, Ananya Choudhury, Sei Chung Sak, D. Timothy Bishop, Heather H. Nelson, Angeline S. Andrew, Margaret R. Karagas, Xifeng Wu, Stephen Chanock, Nuria Malats, Debra Silverman, Manolis Kogevinas, Nathaniel Rothman, Gunnar Steineck, Zuo-Feng Zhang, Donatella Placidi, Jack A. Taylor, Simone Benhamou, Tony Fletcher, Giuseppe Matullo, Jian-Min Yuan, Anne E. Kiltie, Karl T. Kelsey, Jonine D. Figueroa, Jie Lin, and Mariana C. Stern

Abstract

Supplementary Figure Legend from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

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2023
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43. Supplementary Figure 1 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Author

Montserrat Garcia-Closas, Sung Shim Lani Park, Cecilia Arici, Marcello Campagna, Angela Carta, Stefano Porru, Peter Rudnai, Rajiv Kumar, Kvetoslava Koppova, Eugen Gurzau, Alessandra Allione, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Paolo Vineis, Yu-Tang Gao, Yong-Bing Xiang, Victoria K. Cortessis, Manuela Gago-Dominguez, Amit D. Joshi, Román Corral, Faye Elliot, Jennifer H. Barrett, Ananya Choudhury, Sei Chung Sak, D. Timothy Bishop, Heather H. Nelson, Angeline S. Andrew, Margaret R. Karagas, Xifeng Wu, Stephen Chanock, Nuria Malats, Debra Silverman, Manolis Kogevinas, Nathaniel Rothman, Gunnar Steineck, Zuo-Feng Zhang, Donatella Placidi, Jack A. Taylor, Simone Benhamou, Tony Fletcher, Giuseppe Matullo, Jian-Min Yuan, Anne E. Kiltie, Karl T. Kelsey, Jonine D. Figueroa, Jie Lin, and Mariana C. Stern

Abstract

Supplementary Figure 1 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

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2023
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44. Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

Author

Fei Chen, Ravi K. Madduri, Alex A. Rodriguez, Burcu F. Darst, Alisha Chou, Xin Sheng, Anqi Wang, Jiayi Shen, Edward J. Saunders, Suhn K. Rhie, Jeannette T. Bensen, Sue A. Ingles, Rick A. Kittles, Sara S. Strom, Benjamin A. Rybicki, Barbara Nemesure, William B. Isaacs, Janet L. Stanford, Wei Zheng, Maureen Sanderson, Esther M. John, Jong Y. Park, Jianfeng Xu, Ying Wang, Sonja I. Berndt, Chad D. Huff, Edward D. Yeboah, Yao Tettey, Joseph Lachance, Wei Tang, Christopher T. Rentsch, Kelly Cho, Benjamin H. Mcmahon, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Thomas A. Sellers, Kosj Yamoah, Adam B. Murphy, Dana C. Crawford, Alpa V. Patel, William S. Bush, Melinda C. Aldrich, Olivier Cussenot, Gyorgy Petrovics, Jennifer Cullen, Christine M. Neslund-Dudas, Mariana C. Stern, Zsofia Kote-Jarai, Koveela Govindasami, Michael B. Cook, Anand P. Chokkalingam, Ann W. Hsing, Phyllis J. Goodman, Thomas J. Hoffmann, Bettina F. Drake, Jennifer J. Hu, Jacob M. Keaton, Jacklyn N. Hellwege, Peter E. Clark, Mohamed Jalloh, Serigne M. Gueye, Lamine Niang, Olufemi Ogunbiyi, Michael O. Idowu, Olufemi Popoola, Akindele O. Adebiyi, Oseremen I. Aisuodionoe-Shadrach, Hafees O. Ajibola, Mustapha A. Jamda, Olabode P. Oluwole, Maxwell Nwegbu, Ben Adusei, Sunny Mante, Afua Darkwa-Abrahams, James E. Mensah, Halimatou Diop, Stephen K. Van Den Eeden, Pascal Blanchet, Jay H. Fowke, Graham Casey, Anselm J. Hennis, Alexander Lubwama, Ian M. Thompson, Robin Leach, Douglas F. Easton, Michael H. Preuss, Ruth J. Loos, Susan M. Gundell, Peggy Wan, James L. Mohler, Elizabeth T. Fontham, Gary J. Smith, Jack A. Taylor, Shiv Srivastava, Rosaline A. Eeles, John D. Carpten, Adam S. Kibel, Luc Multigner, Marie-Élise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Eric A. Klein, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stefan Ambs, Todd L. Edwards, Stephen Watya, Stephen J. Chanock, John S. Witte, William J. Blot, J. Michael Gaziano, Amy C. Justice, David V. Conti, Christopher A. Haiman, University of Southern California (USC), Keck School of Medicine [Los Angeles], Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], 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
Prostate cancer, MESH: Humans, Urology, MESH: Genetic Predisposition to Disease, MESH: Black People, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Male, Polygenic risk score, African ancestry, MESH: Risk Factors, MESH: Prostatic Neoplasms, MESH: Genome-Wide Association Study, Susceptibility loci, Aggressive prostate cancer
Abstract

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Published
2023
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45. Healthy eating patterns and epigenetic measures of biological age

Author

Yong-Moon Park, Jack A. Taylor, Jean Keller, Dale P. Sandler, and Jacob K. Kresovich

Subjects
Nutrition and Dietetics, Mediterranean diet, business.industry, Biological age, Physical fitness, Medicine (miscellaneous), Healthy eating, Disease, Diet quality, Cohort, Medicine, Epigenetics, business, Demography
Abstract

BACKGROUND Healthy eating is associated with lower risks of disease and mortality, but the mechanisms underlying these associations are unclear. Age is strongly related to health outcomes, and biological age can be estimated using the blood methylome. OBJECTIVES To determine whether healthy eating patterns are associated with methylation-based measures of biological age. METHODS Among women in the Sister Study, we calculated scores on 4 recommendation-based healthy eating indexes [Dietary Approaches to Stop Hypertension diet, Healthy Eating Index-2015, Alternative Healthy Eating Index (aHEI-2010), and the Alternative Mediterranean diet] using a validated 110-item Block FFQ completed at enrollment. Genome-wide DNA methylation data were generated using the HumanMethylation450 BeadChip on whole blood samples collected at enrollment from a case-cohort sample of 2694 women and were used to calculate 4 measures of epigenetic age acceleration (Hannum AgeAccel, Horvath AgeAccel, PhenoAgeAccel, and GrimAgeAccel). Linear regression models, adjusted for covariates and cohort sampling weights, were used to examine cross-sectional associations between eating patterns and measures of biological age. RESULTS All 4 healthy eating indexes had inverse associations with epigenetic age acceleration, most notably with PhenoAgeAccel and GrimAgeAccel. Of these, the strongest associations were for aHEI-2010 [per 1-SD increase in diet quality, PhenoAgeAccel β = -0.5 y (95% CI: -0.8 to -0.2 y) and GrimAgeAccel β = -0.4 y (95% CI: -0.6 to -0.3 y)]. Although effect modification was not observed for most lifestyle factors, in analyses stratified by physical activity, the benefits of a healthy diet on epigenetic age acceleration were more pronounced among women who did not meet physical activity guidelines (reporting

Published
2022
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46. An AAV-CRISPR/Cas9 strategy for gene editing across divergent rodent species: Targeting neural oxytocin receptors as a proof of concept

Author

Arjen J. Boender, Marina Boon, H. Elliott Albers, Samantha R. Eck, Brandon A. Fricker, Aubrey M. Kelly, Joseph E. LeDoux, Simone C. Motta, Prerana Shrestha, Jack H. Taylor, Brian C. Trainor, Rodrigo Triana-Del Rio, and Larry J. Young

Subjects
Multidisciplinary, All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
Abstract

A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches, we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor ( Oxtr ) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species ( n = 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research.

Published
2023

47. Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights

Author

Stella Koutros, Lambertus A. Kiemeney, Parichoy Pal Choudhury, Roger L. Milne, Evangelina Lopez de Maturana, Yuanqing Ye, Vijai Joseph, Oscar Florez-Vargas, Lars Dyrskjøt, Jonine Figueroa, Diptavo Dutta, Graham G. Giles, Michelle A.T. Hildebrandt, Kenneth Offit, Manolis Kogevinas, Elisabete Weiderpass, Marjorie L. McCullough, Neal D. Freedman, Demetrius Albanes, Charles Kooperberg, Victoria K. Cortessis, Margaret R. Karagas, Alison Johnson, Molly R. Schwenn, Dalsu Baris, Helena Furberg, Dean F. Bajorin, Olivier Cussenot, Geraldine Cancel-Tassin, Simone Benhamou, Peter Kraft, Stefano Porru, Angela Carta, Timothy Bishop, Melissa C. Southey, Giuseppe Matullo, Tony Fletcher, Rajiv Kumar, Jack A. Taylor, Philippe Lamy, Frederik Prip, Mark Kalisz, Stephanie J. Weinstein, Jan G. Hengstler, Silvia Selinski, Mark Harland, Mark Teo, Anne E. Kiltie, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina García-Closas, Josep Lloreta, Alan Schned, Petra Lenz, Elio Riboli, Paul Brennan, Anne Tjønneland, Thomas Otto, Daniel Ovsiannikov, Frank Volkert, Sita H. Vermeulen, Katja K. Aben, Tessel E. Galesloot, Constance Turman, Immaculata De Vivo, Edward Giovannucci, David J. Hunter, Chancellor Hohensee, Rebecca Hunt, Alpa V. Patel, Wen-Yi Huang, Gudmar Thorleifsson, Manuela Gago-Dominguez, Pilar Amiano, Klaus Golka, Mariana C. Stern, Wusheng Yan, Jia Liu, Shengchao Alfred Li, Shilpa Katta, Amy Hutchinson, Belynda Hicks, William A. Wheeler, Mark P. Purdue, Katherine A. McGlynn, Cari M. Kitahara, Christopher A. Haiman, Mark H. Greene, Thorunn Rafnar, Nilanjan Chatterjee, Stephen J. Chanock, Xifeng Wu, Francisco X. Real, Debra T. Silverman, Montserrat Garcia-Closas, Kari Stefansson, Ludmila Prokunina-Olsson, Núria Malats, and Nathaniel Rothman

Subjects
Genome-Wide Association Study (GWAS), Germline genetics, All institutes and research themes of the Radboud University Medical Center, Urology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Bladder cancer, Gene-environment interaction
Abstract

Contains fulltext : 293880.pdf (Publisher’s version ) (Closed access) BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p

Published
2023
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48. Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

Author

Tina Pesaran, Jeffrey N. Weitzel, Clarice R. Weinberg, Chi Gao, Susan L. Neuhausen, Eric C. Polley, Alpa V. Patel, Christopher A. Haiman, Christine B. Ambrosone, Celine M. Vachon, Hongyan Huang, Sara Lindstrom, Julie R. Palmer, Esther M. John, Jill S. Dolinsky, Leslie Bernstein, Rohan Gnanaolivu, Allison W. Kurian, Steven N. Hart, Holly LaDuca, Hoda Anton-Culver, Janet E. Olson, Chunling Hu, Amal Yussuf, Song Yao, Nicole L. Larson, Peter Kraft, Jie Na, Fergus J. Couch, Nicholas J. Boddicker, Elena Martinez, Amy Trentham-Dietz, Siddhartha Yadav, Paul W. Auer, Dale R Sandler, Elizabeth C. Chao, Susan M. Domchek, Rachid Karam, Katherine L. Nathanson, James V. Lacey, Jack A. Taylor, and David E. Goldgar

Subjects
Adult, Cancer Research, Adolescent, Breast Neoplasms, Germline, Young Adult, Biomarkers, Tumor, Humans, Medicine, Genetic Predisposition to Disease, Genetic Testing, skin and connective tissue diseases, Gene, Germ-Line Mutation, Aged, Aged, 80 and over, business.industry, Cancer predisposition, Carcinoma, Ductal, Breast, ORIGINAL REPORTS, Middle Aged, Prognosis, medicine.disease, body regions, Carcinoma, Lobular, Oncology, Case-Control Studies, Invasive lobular carcinoma, cardiovascular system, Cancer research, Female, Hereditary Cancer, business, Follow-Up Studies
Abstract

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

Published
2021
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49. Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use

Author

Fang Fang, Bryan Quach, Kaitlyn G. Lawrence, Jenny van Dongen, Jesse A. Marks, Sara Lundgren, Mingkuan Lin, Veronika V. Odintsova, Ricardo Costeira, Zongli Xu, Linran Zhou, Meisha Mandal, Yujing Xia, Jacqueline M. Vink, Laura J Bierut, Miina Ollikainen, Jack A. Taylor, Jordana T. Bell, Jaakko Kaprio, Dorret I. Boomsma, Ke Xu, Dale P. Sandler, Dana B. Hancock, and Eric O. Johnson

Abstract

Cannabis is widely used worldwide, yet its links to health outcomes are not fully understood. DNA methylation can serve as a mediator to link environmental exposures to health outcomes. We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and lifetime cannabis use (ever vs. never) in a meta-analysis including 9,436 participants (7,795 European and 1,641 African ancestry) from seven cohorts. Accounting for effects of cigarette smoking, our trans-ancestry EWAS meta-analysis revealed four CpG sites significantly associated with lifetime cannabis use at a false discovery rate of 0.05 (p< 5.85 × 10−7): cg22572071 near geneADGRF1, cg15280358 inADAM12, cg00813162 inACTN1, and cg01101459 nearLINC01132. Additionally, our EWAS analysis in participants who never smoked cigarettes identified another epigenome-wide significant CpG site, cg14237301 annotated toAPOBR. We used a leave-one-out approach to evaluate methylation scores constructed as a weighted sum of the significant CpGs. The best model can explain 3.79% of the variance in lifetime cannabis use. These findings unravel the DNA methylation changes associated with lifetime cannabis use that are independent of cigarette smoking and may serve as a starting point for further research on the mechanisms through which cannabis exposure impacts health outcomes.

Published
2022
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50. Baseline Reliability and Six‐Month Stability of a Remotely Administered Battery of Smartphone Cognitive Tests

Author

Jack C Taylor, Annie L Clark, Hilary W. Heuer, Amy B Wise, Masood Manoochehri, Leah K. Forsberg, Carly T. Mester, Meghana Rao, Danielle Brushaber, Joel H. Kramer, Bradley F. Boeve, Howard J. Rosen, Adam L. Boxer, and Adam M. Staffaroni

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022
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