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1. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author

Vesa Kataja, Aida Karina Dieffenbach, Chia-Ni Hsiung, Catherine S. Healey, Gie Hooi Tan, Soo Hwang Teo, Domenico Palli, Frederik Marme, Katri Pylkäs, Roger L. Milne, Jaana M. Hartikainen, Gord Glendon, Susan L. Slager, Chen-Yang Shen, Fredrick R. Schumacher, Daniel F. Schmidt, Suleeporn Sangrajrang, Kee Seng Chia, Lorna Gibson, Pascal Guénel, Alice S. Whittemore, Jenny Chang-Claude, Yu Tang Gao, Hidemi Ito, Simon S. Cross, Sofia Khan, Marie Sanchez, Daniel Vincent, Daniel Herrero, Nicola Miller, Antoinette Hollestelle, Caroline M. Seynaeve, Christopher A. Haiman, Hermann Brenner, Kay-Tee Khaw, Loris Bernard, Habibul Ahsan, Melissa C. Southey, David Van Den Berg, Martha J. Shrubsole, Daniel O. Stram, William Blot, Mel Maranian, Robert Winqvist, Keitaro Matsuo, John W. M. Martens, Heli Nevanlinna, Mia M. Gaudet, Anna Jakubowska, Christine D. Berg, Paul D.P. Pharoah, Jacques Simard, Manjeet K. Bolla, Dieter Flesch-Janys, Mark S. Goldberg, Paul Brennan, Ching Wan Chan, Sune F. Nielsen, Sara Lindström, Mitul Shah, Matthias W. Beckmann, Craig Luccarini, Jonathan Beesley, Kyriaki Michailidou, Paolo Peterlongo, Marc J. Gunter, Anna González-Neira, Ji Yeob Choi, Per Hall, Sarah Stewart-Brown, Keith Humphreys, Hui Cai, Kathleen E. Malone, Elinor J. Sawyer, Louise A. Brinton, Marjanka K. Schmidt, Xiao-Ou Shu, Barbara Perkins, Lotte Maxild Mortensen, Chiu-Chen Tseng, Hanne Meijers-Heijboer, Minouk J. Schoemaker, Keun-Young Yoo, Julia A. Knight, Alan Ashworth, Stig E. Bojesen, Kamila Czene, Artitaya Lophatananon, Graham G. Giles, S. Ahmed, Kazuo Tajima, Douglas F. Easton, Maria Kabisch, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Irene L. Andrulis, Clare Turnbull, Caroline Baynes, Christine B. Ambrosone, Jan Lubinski, Muriel A. Adank, A. Meindl, Taru A. Muranen, Siranoush Manoukian, Susan M. Gapstur, Natalia Bogdanova, Alexander Hein, Annika Lindblom, Nazneen Rahman, Annegien Broeks, Lothar Haeberle, Federico Canzian, G Pita, Ming-Feng Hou, Hiroji Iwata, Drakoulis Yannoukakos, Diana Torres, Vessela N. Kristensen, Peter Devilee, Qiuyin Cai, Christi J Asperen, John L. Hopper, Diether Lambrechts, Michael Lush, Hans Wildiers, Joe Dennis, Sandra L. Halverson, Carl Blomqvist, Erik Van Limbergen, Malin Sund, Daehee Kang, Grethe I. Grenaker Alnæs, Marilie D. Gammon, Ursula Eilber, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Kirsimari Aaltonen, Olivia Fletcher, Jonine D. Figueroa, Angela Cox, Pei Ei Wu, Maartje J. Hooning, Catriona McLean, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Malcolm W.R. Reed, Emily Hallberg, Sara Margolin, Volker Arndt, Montserrat Garcia-Closas, Francois Bacot, Rita K. Schmutzler, Julian Peto, David J. Hunter, Thomas Brüning, Katarzyna Jaworska, Christof Sohn, Børge G. Nordestgaard, Enes Makalic, Hatef Darabi, Barbara Burwinkel, Petra P.H. Peeters, J. Margriet Collée, Rongxi Yang, Robert N. Hoover, Eiliv Lund, Fergus J. Couch, Ute Hamann, Jirong Long, Wei Zheng, Sabine Behrens, Giske Ursin, Muhammad G. Kibriya, Claire Mulot, Laure Dossus, Helen Tsimiklis, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Alison M. Dunning, Lisa B. Signorello, Valerie Gaborieau, Kenneth Muir, Anthony J. Swerdlow, Javier Benitez, Judith S. Brand, Sander Canisius, Hoda Anton-Culver, Veli-Matti Kosma, Thilo Dörk, Sten Cornelissen, Christa Stegmaier, Cheng Har Yip, Brian E. Henderson, Harald Surowy, Jingmei Li, Nur Aishah Taib, W. Ryan Diver, Carmel Apicella, Janet E. Olson, Kristiina Aittomäki, Celine M. Vachon, Regina M. Santella, Dimitrios Trichopoulos, Jianjun Liu, Nick Orr, Martine Dumont, Christian Sutter, Sue K. Park, Mikael Hartman, Susan L. Neuhausen, Hui Miao, M. Pilar Zamora, Anna H. Wu, Rob B. van der Luijt, Isabel dos-Santos-Silva, Graham Casey, Henrik Flyger, M. Rosario Alonso, Nuria Álvarez, Michael J. Kerin, Loic Le Marchand, Jose Ignacio Arias Perez, Mikael Eriksson, Esther M. John, Quinten Waisfisz, Qin Wang, Daniel C. Tessier, Paolo Radice, Robert A.E.M. Tollenaar, James McKay, Silje Nord, Hiltrud Brauch, José María Huerta, Stephen J. Chanock, Mervi Grip, Patrick Neven, Senno Verhoef, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, and CCA - Oncogenesis

Subjects
Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Biology, Research Support, Polymorphism, Single Nucleotide, N.I.H, Cohort Studies, brca1, Breast cancer, Research Support, N.I.H., Extramural, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, common variants, Journal Article, estrogen, chek2-asterisk-1100delc, Genetics, medicine, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Non-U.S. Gov't, genotype imputation, risk, Genetic association, Research Support, Non-U.S. Gov't, Chromatin binding, Extramural, Cancer, Microarray Analysis, confer susceptibility, medicine.disease, 3. Good health, ovarian-cancer, Genetic Loci, Case-Control Studies, alleles, Female, Imputation (genetics), Genome-Wide Association Study, metaanalysis
Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published

Published
2015
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2. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Author

Laurie Burdette, Rick A. Kittles, Hidewaki Nakagawa, Janet L. Stanford, Wojciech Kluźniak, Karen Park, Sofia Maia, Lisa A. Cannon-Albright, Douglas F. Easton, Dennis J. Hazelett, Hermann Brenner, Paula Paulo, Peter Klarskov, Zhaoming Wang, Koveela Govindasami, Loic Le Marchand, David V. Conti, Phyllis J. Goodman, Chavdar Slavov, Manuel R. Teixeira, Sara Lindström, Maren Weischer, Suzanne Kolb, Lisa B. Signorello, Jianfeng Xu, W. Ryan Diver, Barbara Nemesure, Fredrick R. Schumacher, Michael B. Cook, Qiyuan Li, William J. Blot, Jyotsna Batra, Malgorzata Tymrakiewicz, Anand P. Chokkalingam, Esther M. John, Christopher A. Haiman, Merideth Yeager, David E. Neal, John D. Carpten, Daniel Leongamornlert, Cezary Cybulski, Kathryn L. Penney, Sara Benlloch, Peter Iversen, Judith A. Clements, Shannon K. McDonnell, Matthew L. Freedman, Adam B. Murphy, Mahbubl Ahmed, Kenneth Muir, Sonja I. Berndt, Aida Karina Dieffenbach, Cristina Leske, William B. Isaacs, Chee Goh, Edward D. Yeboah, Jong Y. Park, Ruth C. Travis, Atsushi Takahashi, Nora Pashayan, Timothy J. Key, Evelyn Tay, Lorelei A. Mucci, Edward Giovannucci, Stephen N. Thibodeau, Fredrik Wiklund, Amanda B. Spurdle, Teuvo L.J. Tammela, Peter Kraft, Johanna Schleutker, Melissa C. Southey, Elio Riboli, Afshan Siddiq, Sara S. Strom, Hardev Pandha, Curtis A. Pettaway, Sue A. Ingles, Demetrius Albanes, Brian E. Henderson, Rosalind A. Eeles, Meir J. Stampfer, Markus Aly, Suh-Yuh Wu, Constance Chen, Sune F. Nielsen, Federico Canzian, Christa Stegmaier, Hui-Yi Lin, Amy K. Hutchinson, John S. Witte, Andrzej M. Kierzek, Elizabeth M. Gillanders, Vanio Mitev, Dominika Wokołorczyk, Ali Amin Al Olama, Richard B. Biritwum, Andrew A. Adjei, Ann Truelove, Daniel J. Schaid, Mitchell J. Machiela, Graham Casey, Børge G. Nordestgaard, Wei Zheng, Tokhir Dadaev, Thomas A. Sellers, Lucy Xia, Antonio Hurtado Coll, Tiina Wahlfors, Paul D.P. Pharoah, Jenny L Donovan, Victoria L. Stevens, Kristin A. Rand, Kai Yu, Alex Stram, Anssi Auvinen, Lisa Chu, Adam S. Kibel, Yao Tettey, Gerhard A. Coetzee, Martin Andreas Røder, Gianluca Severi, Daniel O. Stram, Anselm Hennis, Charles C. Chung, Jing Ma, Stephen J. Chanock, Katri A. Leinonen, Stephanie J. Weinstein, Jonathan Tyrer, Freddie C. Hamdy, Shelley Niwa, Kathleen Herkommer, Beatrice S. Knudsen, Laurence N. Kolonel, David J. Hunter, Christine Neslund-Dudas, Loreall Pooler, Robert N. Hoover, Antje E. Rinckleb, Jarmo Virtamo, Henrik Grönberg, Peggy Wan, Eric A. Klein, Michelle Guy, Manuel Luedeke, Radka Kaneva, Xin Sheng, Zsofia Kote-Jarai, Daniella Seminara, Tapio Visakorpi, Christiane Maier, Ann W. Hsing, Susan M. Gapstur, Sara Jugurnauth-Little, Ying Han, Ed Saunders, Agnieszka Michael, Alan W. Partin, Graham G. Giles, S. Lilly Zheng, Michiaki Kubo, Benjamin A. Rybicki, Kay-Tee Khaw, and Sarah K. Holt

Subjects
Male, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Disease, Biology, ta3111, Polymorphism, Single Nucleotide, Risk Assessment, Article, Prostate cancer, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic association, ta113, ta112, ta1184, ta1182, Cancer, Prostatic Neoplasms, medicine.disease, ta3122, Genetic Loci, Meta-analysis, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Published
2014

3. A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry

Author

Mary Cushman, Shad B. Smith, Patricia A. Peyser, Jorge L. Rodriguez-Gil, Struan F.A. Grant, Regina G. Ziegler, Timothy D. Howard, Imran O. Morhason-Bello, Mariaelisa Graff, Christopher S. Carlson, Cameron D. Palmer, Charleston W. K. Chiang, Evandine Rampersaud, Lisa Chu, Uma Nayak, Curtis A. Pettaway, Ye Feng, Jing Hua Zhao, Barbara V. Howard, Joanne M. Jordan, Gregory L. Burke, Melinda C. Aldrich, Dezheng Huo, Omri Gottesman, Richard S. Cooper, Sonja I. Berndt, Donna K. Arnett, Gary S. Gilkeson, M. Cristina Leske, Ulrich Broeckel, Edmond K. Kabagambe, Stephen J. Chanock, Michael J. Thun, John S. Witte, William Maixner, Adebowale Adeyemo, Oladosu Ojengbede, Sarah J. Nyante, William J. Blot, Nicholette D. Palmer, Jyotika K. Fernandes, Laura J. Rasmussen-Torvik, Julie R. Palmer, Ida J. Spruill, Wei Zheng, Ruth J. F. Loos, Guo Li, Robert C. Millikan, Donald W. Bowden, Ellen W. Demerath, Michèle M. Sale, Neil A. Zakai, Zhaoming Wang, Fang Chen, George J. Papanicolaou, Gary K. Chen, Talin Haritunians, Rajiv Nadukuru, James J. Yang, Brian E. Henderson, Sandra Deming-Halverson, Adesola Ogunniyi, David Van Den Berg, Diane L. Kamen, Phyllis J. Goodman, Eric A. Klein, Yingchang Lu, Thomas W. Winkler, Marguerite R. Irvin, Badri Padhukasahasram, Benjamin A. Rybicki, Yan V. Sun, Yii-Der Ida Chen, Temidayo O. Ogundiran, Andrew B. Singleton, Babatunde L. Salako, Vaneet Lotay, Christine B. Ambrosone, Karen C. Johnson, Michael F. Press, Neil E. Caporaso, Guillaume Lettre, Ingrid B. Borecki, Sue A. Ingles, Yonglan Zheng, Jennifer J. Hu, Leslie Bernstein, Keri L. Monda, Kristine R. Monroe, L. Keoki Williams, Thomas H. Mosley, Shamika Ketkar, Ryan W. Driver, Margaret A. Tucker, Josyf C. Mychaleckyj, Ann W. Hsing, Xiuqing Guo, Lewis H. Kuller, Patricia M. Dubbert, Kelly J. Hunt, JoAnn E. Manson, Joel N. Hirschhorn, Mara Z. Vitolins, Tamara B. Harris, Matthew A. Allison, Abdullah Kutlar, Leslie A. Lange, Yongmei Liu, Ulrike Peters, Hakon Hakonarson, Mary K. Wojczynski, Xiaofeng Zhu, Edward A. Ruiz-Narváez, Todd L. Edwards, Heather M. Ochs-Balcom, Jingzhong Ding, Albert M. Levin, W. Timothy Garvey, Digna R. Velez Edwards, Sun J. Kang, Jie Zhou, Barry I. Freedman, Sanjay R. Patel, Suh Yuh Wu, Sylvia Wassertheil-Smoller, Simin Liu, Daniel Shriner, Elizabeth K. Speliotes, Larry D. Atwood, Graham Casey, Lisa R. Yanek, Susan Redline, Lisa B. Signorello, Wei Zhao, Scott M. Williams, Bamidele O. Tayo, Kira C. Taylor, Angela Britton, Xifeng Wu, Erwin P. Bottinger, Charles N. Rotimi, Mary F. Feitosa, Joseph M. Zmuda, Curtis C. Harris, Christine Neslund-Dudas, Bruce M. Psaty, Alexander P. Reiner, Helen N. Lyon, Youfang Liu, Krista A. Zanetti, Jonathan P. Bradfield, Esther M. John, Ann G. Schwartz, Elizabeth M. Gillanders, Mike A. Nalls, Suzanne Kolb, Cathryn H. Bock, Alan B. Zonderman, David Duggan, Gerhard A. Coetzee, Charles Kooperberg, Sharon L.R. Kardia, Olufunmilayo I. Olopade, Suhn K. Rhie, John D. Carpten, Maggie C.Y. Ng, Kari E. North, Christopher A. Haiman, Barbara Nemesure, Loic Le Marchand, Christopher I. Amos, Adeyinka Ademola, Lara Sucheston, Pamela J. Schreiner, Taylor Young, Sara S. Strom, Carl D. Langefeld, Jason H. Moore, Marian L. Neuhouser, Lawrence F. Bielak, Diane M. Becker, Margaret Wrensch, Janet L. Stanford, Laurence N. Kolonel, Yan A. Meng, Margaret R. Spitz, Brendan J. Keating, Kurt Lohman, Virginia J. Howard, Guanjie Chen, Elisa V. Bandera, Quiyin Cai, Amidou N'Diaye, Stefan Ambs, Adam B. Murphy, Eric E. Schadt, Anselm Hennis, Rick A. Kittles, Caroline S. Fox, John K. Wiencke, Katherine L. Nathanson, Barbara McKnight, Michele K. Evans, Wei-Min Chen, Dena G. Hernandez, Herman A. Taylor, David S. Siscovick, and Lorna H. McNeill

Subjects
Genetics, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, FTO gene, Linkage Disequilibrium, Article, Body Mass Index, Black or African American, Gene Frequency, Genetic Loci, Case-Control Studies, Meta-analysis, Genetic variation, Humans, Genetic Predisposition to Disease, Obesity, Body mass index, Genome-Wide Association Study, Genetic association
Abstract

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

Published
2013
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4. Genome-wide association analyses in east Asians identify new susceptibility loci for colorectal cancer

Author

Ji Won Park, Yu-Tang Gao, Ben Zhang, Honglan Li, Qiuyin Cai, Satoyo Hosono, Jae Hwan Oh, Ryan J. Delahanty, Graham Casey, Jiajun Shi, Wei Zheng, Yong-Bing Xiang, Aesun Shin, Yi Xin Zeng, Ulrike Peters, Dong Hyun Kim, Zefang Ren, Gong Yang, Fumihiko Matsuda, Keitaro Matsuo, Eun Jung Park, Jin Young Jeong, Yoon-Ok Ahn, Jaeseong Jo, Xiao-Ou Shu, Zhi Zhong Pan, Jirong Long, Bu Tian Ji, Sun Ha Jee, Wanqing Wen, and Wei Hua Jia

Subjects
Genotype, Colorectal cancer, Population, Chromosomes, Human, Pair 20, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Genome, White People, Article, 03 medical and health sciences, 0302 clinical medicine, Asian People, Polymorphism (computer science), Odds Ratio, Genetics, medicine, Cyclin D2, Humans, Genetic Predisposition to Disease, education, 030304 developmental biology, Principal Component Analysis, 0303 health sciences, education.field_of_study, Chromosomes, Human, Pair 12, Asia, Eastern, Genome, Human, Odds ratio, medicine.disease, Human genetics, 3. Good health, Genetics, Population, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

To identify new genetic factors for colorectal cancer (CRC), we conducted a genome-wide association study in east Asians. By analyzing genome-wide data in 2,098 cases and 5,749 controls, we selected 64 promising SNPs for replication in an independent set of samples, including up to 5,358 cases and 5,922 controls. We identified four SNPs with association P values of 8.58 × 10(-7) to 3.77 × 10(-10) in the combined analysis of all east Asian samples. Three of the four were replicated in a study conducted in 26,060 individuals of European descent, with combined P values of 1.22 × 10(-10) for rs647161 (5q31.1), 6.64 × 10(-9) for rs2423279 (20p12.3) and 3.06 × 10(-8) for rs10774214 (12p13.32 near the CCND2 gene), derived from meta-analysis of data from both east Asian and European-ancestry populations. This study identified three new CRC susceptibility loci and provides additional insight into the genetics and biology of CRC.

Published
2012
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5. Principles for the post-GWAS functional characterization of cancer risk loci

Author

Christoph Plass, Simon A. Gayther, Alvaro N.A. Monteiro, Gerhard A. Coetzee, Haris G. Vikis, Christopher S. Carlson, Mariella De Biasi, Ming You, Graham Casey, Matthew L. Freedman, Michael A. James, Pengyuan Liu, Jay W. Tichelaar, Ian G. Mills, David Duggan, and Angela Risch

Subjects
Genetics, Candidate gene, Linkage disequilibrium, Expression quantitative trait loci, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Biology, Tag SNP, Common disease-common variant
Abstract

Genome wide association studies (GWAS) have identified more than 200 mostly new common low-penetrance susceptibility loci for cancers. The predicted risk associated with each locus is generally modest (with a per-allele odds ratio typically less than 2) and so, presumably, are the functional effects of individual genetic variants conferring disease susceptibility. Perhaps the greatest challenge in the ‘post-GWAS’ era is to understand the functional consequences of these loci. Biological insights can then be translated to clinical benefits, including reliable biomarkers and effective strategies for screening and disease prevention. The purpose of this article is to propose principles for the initial functional characterization of cancer risk loci, with a focus on non-coding variants, and to define ‘post-GWAS’ functional characterization. By December 2010, there were 1,212 published GWAS studies1 reporting significant (P < 5 × 10−8) associations for 210 traits (Table 1), and the Catalog of Published GWAS states that by March 2011, 812 publications reported 3,977 SNP associations1. This is likely a small fraction of the common susceptibility loci of low penetrance that will eventually be identified. Despite these successes in identifying risk loci, the causal variant and/or the molecular basis of risk etiology has been determined for only a small fraction of these associations2–4. Plausible candidate genes can be based on proximity to risk loci, but few have so far been defined in a more systematic manner (Supplementary Table 1). Table 1 The genomic context in which a variant is found can be used as preliminary functional analysis Increased investment in post-GWAS functional characterization of risk loci5 has now been advocated across diseases and for cardiovascular disease and diabetes6. For cancer biology, the complex interplay between genetics and the environment in many cancers poses a particularly exciting challenge for post-GWAS research. Here we suggest a systematic strategy for understanding how cancer-associated variants exert their effects. We mostly refer to SNPs throughout the paper, but we recognize that other types of common genetic (for example, copy number variants) or epigenetic variation may influence risk. Our understanding of the way in which a risk variant initiates disease pathogenesis progresses from statistical association between genetic variation and trait or disease variation to functionality and causality. The functional consequences of variants in protein-coding regions causing most monogenic disorders are more readily interpreted because we know the genetic code. For non-Mendelian or multifactorial traits, most of the common DNA variants have so far mapped to non-protein–coding regions2, where our understanding of functional consequences and causality is more rudimentary. Our hypothesis is that the trait-associated alleles exert their effects by influencing transcriptional output (such as transcript levels and splicing) through multiple mechanisms. We emphasize appropriate assays and models to test the functional effects of both SNPs and genes mapping to cancer predisposition loci. Although much of what is written is applicable to alleles discovered for any trait, the section on modeling gene effects will emphasize measuring cancer-related phenotypes. At some loci, multiple, independently associated risk alleles rather than single risk alleles may be functionally responsible for the occurrence of disease. Genotyping susceptibility loci (and their correlated variants) in multiple populations with different linkage disequilibrium (LD) structures may prove effective in substantially reducing the number of potentially causative variants (that is, the same causal variant may segregate in multiple populations), as shown for the FGFR2 locus in breast cancer7, but for most loci there will remain a set of potentially causative variants that cannot be separated at the statistical level from case-control genotype data. A susceptibility locus should be re-sequenced to ascertain all genetic variation, identifying candidate functional or causal variants and identifying candidate causal genes. Ideally, the identification of a causal SNP would be the next step to reveal the molecular mechanisms of risk modification. Practically, however, it is unclear what the criteria for causality should be, particularly in non-protein–coding regions. Thus, although we propose a framework set of analyses (Box 1), we acknowledge that the techniques and methods will continue to evolve with the field. Box 1 Strategies to progress from tag SNP to mechanism Target resequencing efforts using linkage disequilibrium (LD) structure. Use other populations to refine LD regions (for example African ancestry with shorter LD and more heterogeneity). Determine expression levels of nearby genes as a function of genotype at each locus (eQTL). Characterize gene regulatory regions by multiple empirical techniques bearing in mind that these are tissue and context specific. Combine regulatory regions with risk loci using coordinates from multiple reference genomes to capture all variation within the shorter regulatory regions that correlates with the tag SNP at each locus. Multiple experimental manipulations in model systems are needed to progressively implicate transcription units (genes) in mechanisms relevant to the associated loci: Knockouts of regulatory regions in animal (difficult and may be limited by functional redundancy, but new targeting methods in rat are promising) models followed by genome-wide expression analysis. Use chromatin association methods (3C, CHIA-PET) of regulatory regions to determine the identity of target genes (compare with eQTL data). Targeted gene perturbations in somatic cell models. Explore fully genome-wide eQTL and miRNA quantitative variation correlation in relevant tissues and cells. Explore epigenetic mechanisms in the context of genome-wide genetic polymorphism. Employ cell models and tissue reconstructions to evaluate mechanisms using gene perturbations and polymorphic variants. The human cancer cell xenograft has re-emerged as a minimal in vivo validation of these models. Above all, resist the temptation to equate any partial functional evidence as sufficient. Published claims of functional relevance should be fully evaluated using the steps detailed above.

Published
2011
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6. Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21

Author

Iona Cheng, Stephen Watya, Anna M. Ray, Timothy R. Rebbeck, Kristine R. Monroe, John S. Witte, Sara S. Strom, Yuko Yamamura, John D. Carpten, Brian E. Henderson, Ann W. Hsing, Janet L. Stanford, Peggy Wan, M. Cristina Leske, Edder R. Duarte, Sonja I. Berndt, Loreall Pooler, William J. Blot, Charnita Zeigler-Johnson, Zhaoming Wang, Venetta Thomas, Stephen J. Chanock, David Van Den Berg, W. Ryan Diver, Richard B. Hayes, Michael J. Thun, Graham Casey, Benjamin A. Rybicki, Christopher A. Haiman, Sue A. Ingles, Bao Li Chang, Jennifer J. Hu, Kathleen A. Cooney, Qiuyin Cai, Barbara Nemesure, Loic Le Marchand, William B. Isaacs, Gary K. Chen, Jennifer Haslag-Minoff, Esther M. John, S. Lilly Zheng, Glenn O. Allen, Xin Sheng, Suh Yuh Wu, Laurence N. Kolonel, Erin N. Carter, Elaine A. Ostrander, Christine Neslund-Dudas, Suzanne Kolb, Lisa B. Signorello, Yao Tettey, Adam B. Murphy, Rick A. Kittles, Jianfeng Xu, Fredrick R. Schumacher, William Wu, Lucy Xia, Adam S. Kibel, Daniel O. Stram, Anselm Hennis, Edward D. Yeboah, and Serigne Magueye Gueye

Subjects
Male, Genome-wide association study, Disease, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, 030304 developmental biology, Genetic association, 0303 health sciences, Prostatic Neoplasms, Chromosome, Cancer, Odds ratio, medicine.disease, 3. Good health, Black or African American, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (

Published
2011
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7. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases

Author

Ying Xiang, Robert H. Silverman, Phillippa J. Neville, Sarah J. Plummer, Nina N. Nupponen, John D. Carpten, Jeffrey M. Trent, Eric A. Klein, John S. Witte, Lisa M. Krumroy, Graham Casey, and William J. Catalona

Subjects
Male, Heterozygote, DNA Mutational Analysis, Gene Dosage, Arginine, Xenotropic murine leukemia virus-related virus, MSR1, Prostate cancer, Prostate, Endoribonucleases, Genetics, medicine, Humans, Point Mutation, Genetic Predisposition to Disease, Allele, Germ-Line Mutation, Aged, biology, Homozygote, Wild type, RNASEL Gene, Prostatic Neoplasms, Middle Aged, Prostate-Specific Antigen, medicine.disease, biology.organism_classification, Pedigree, medicine.anatomical_structure, Amino Acid Substitution, Case-Control Studies, Cancer research, biology.protein, Ribonuclease L, Gene Deletion
Abstract

RNASEL (encoding ribonuclease L) has recently been proposed as a candidate for the hereditary prostate cancer (HPC1) gene. We determined that the RNASEL variant Arg462Gln has three times less enzymatic activity than the wildtype and is significantly associated with prostate cancer risk (P = 0.007). At least one copy of the mutated allele that causes this substitution is carried by nearly 60% of the men in our study. Men that are heterozygous with respect to the mutated allele have 50% greater risk of prostate cancer than non-carriers, and homozygotes have more than double the risk.

Published
2002

8. Breast cancer information on the web

Author

Stephen H. Friend, Barbara L. Weber, David E. Goldgar, Pat Murphy, Simon A. Gayther, Peter Devilee, Larry Brody, Roger W Wiseman, Graham Casey, and Anne Lise Børresen

Subjects
Oncology, medicine.medical_specialty, BRCA1 Protein, Breast Neoplasms, Biology, medicine.disease, Neoplasm Proteins, Computer Communication Networks, Breast cancer, Internal medicine, Mutation, Genetics, medicine, Humans, DNA Primers, Transcription Factors
Published
1995
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