المؤلفون: Suzuki, Ken, Hatzikotoulas, Konstantinos, Southam, Lorraine, Taylor, Henry J, Yin, Xianyong, Lorenz, Kim M, Mandla, Ravi, Huerta-Chagoya, Alicia, Melloni, Giorgio EM, Kanoni, Stavroula, Rayner, Nigel W, Bocher, Ozvan, Arruda, Ana Luiza, Sonehara, Kyuto, Namba, Shinichi, Lee, Simon SK, Preuss, Michael H, Petty, Lauren E, Schroeder, Philip, Vanderwerff, Brett, Kals, Mart, Bragg, Fiona, Lin, Kuang, Guo, Xiuqing, Zhang, Weihua, Yao, Jie, Kim, Young Jin, Graff, Mariaelisa, Takeuchi, Fumihiko, Nano, Jana, Lamri, Amel, Nakatochi, Masahiro, Moon, Sanghoon, Scott, Robert A, Cook, James P, Lee, Jung-Jin, Pan, Ian, Taliun, Daniel, Parra, Esteban J, Chai, Jin-Fang, Bielak, Lawrence F, Tabara, Yasuharu, Hai, Yang, Thorleifsson, Gudmar, Grarup, Niels, Sofer, Tamar, Wuttke, Matthias, Sarnowski, Chloé, Gieger, Christian, Nousome, Darryl, Trompet, Stella, Kwak, Soo-Heon, Long, Jirong, Sun, Meng, Tong, Lin, Chen, Wei-Min, Nongmaithem, Suraj S, Noordam, Raymond, Lim, Victor JY, Tam, Claudia HT, Joo, Yoonjung Yoonie, Chen, Chien-Hsiun, Raffield, Laura M, Prins, Bram Peter, Nicolas, Aude, Yanek, Lisa R, Chen, Guanjie, Brody, Jennifer A, Kabagambe, Edmond, An, Ping, Xiang, Anny H, Choi, Hyeok Sun, Cade, Brian E, Tan, Jingyi, Broadaway, K Alaine, Williamson, Alice, Kamali, Zoha, Cui, Jinrui, Thangam, Manonanthini, Adair, Linda S, Adeyemo, Adebowale, Aguilar-Salinas, Carlos A, Ahluwalia, Tarunveer S, Anand, Sonia S, Bertoni, Alain, Bork-Jensen, Jette, Brandslund, Ivan, Buchanan, Thomas A, Burant, Charles F, Butterworth, Adam S, Canouil, Mickaël, Chan, Juliana CN, Chang, Li-Ching, Chee, Miao-Li, Chen, Ji, Chen, Shyh-Huei, Chen, Yuan-Tsong, Chen, Zhengming, Chuang, Lee-Ming, Cushman, Mary, Danesh, John, Das, Swapan K, de Silva, H Janaka, Dedoussis, George, Dimitrov, Latchezar, Doumatey, Ayo P, Du, Shufa, Duan, Qing, Eckardt, Kai-Uwe, Emery, Leslie S, Evans, Daniel S, Evans, Michele K, Fischer, Krista, Floyd, James S, Ford, Ian, Franco, Oscar H, Frayling, Timothy M, Freedman, Barry I, Genter, Pauline, Gerstein, Hertzel C, Giedraitis, Vilmantas, González-Villalpando, Clicerio, González-Villalpando, Maria Elena, Gordon-Larsen, Penny, Gross, Myron, Guare, Lindsay A, Hackinger, Sophie, Hakaste, Liisa, Han, Sohee, Hattersley, Andrew T, Herder, Christian, Horikoshi, Momoko, Howard, Annie-Green, Hsueh, Willa, Huang, Mengna, Huang, Wei, Hung, Yi-Jen, Hwang, Mi Yeong, Hwu, Chii-Min, Ichihara, Sahoko, Ikram, Mohammad Arfan, Ingelsson, Martin, Islam, Md Tariqul, Isono, Masato, Jang, Hye-Mi, Jasmine, Farzana, Jiang, Guozhi, Jonas, Jost B, Jørgensen, Torben, Kamanu, Frederick K, Kandeel, Fouad R, Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kaur, Varinderpal, Kawaguchi, Takahisa, Keaton, Jacob M, Kho, Abel N, Khor, Chiea-Chuen, Kibriya, Muhammad G, Kim, Duk-Hwan, Kronenberg, Florian, Kuusisto, Johanna, Läll, Kristi, Lange, Leslie A, Lee, Kyung Min, Lee, Myung-Shik, Lee, Nanette R, Leong, Aaron, Li, Liming, Li, Yun, Li-Gao, Ruifang, Ligthart, Symen, Lindgren, Cecilia M, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Locke, Adam E, Louie, Tin, Luan, Jian'an, Luk, Andrea O, Luo, Xi, Lv, Jun, Lynch, Julie A, Lyssenko, Valeriya, Maeda, Shiro, Mamakou, Vasiliki, Mansuri, Sohail Rafik, Matsuda, Koichi, Meitinger, Thomas, Melander, Olle, Metspalu, Andres, Mo, Huan, Morris, Andrew D, Moura, Filipe A, Nadler, Jerry L, Nalls, Michael A, Nayak, Uma, Ntalla, Ioanna, Okada, Yukinori, Orozco, Lorena, Patel, Sanjay R, Patil, Snehal, Pei, Pei, Pereira, Mark A, Peters, Annette, Pirie, Fraser J, Polikowsky, Hannah G, Porneala, Bianca, Prasad, Gauri, Rasmussen-Torvik, Laura J, Reiner, Alexander P, Roden, Michael, Rohde, Rebecca, Roll, Katheryn, Sabanayagam, Charumathi, Sandow, Kevin, Sankareswaran, Alagu, Sattar, Naveed, Schönherr, Sebastian, Shahriar, Mohammad, Shen, Botong, Shi, Jinxiu, Shin, Dong Mun, Shojima, Nobuhiro, Smith, Jennifer A, So, Wing Yee, Stančáková, Alena, Steinthorsdottir, Valgerdur, Stilp, Adrienne M, Strauch, Konstantin, Taylor, Kent D, Thorand, Barbara, Thorsteinsdottir, Unnur, Tomlinson, Brian, Tran, Tam C, Tsai, Fuu-Jen, Tuomilehto, Jaakko, Tusie-Luna, Teresa, Udler, Miriam S, Valladares-Salgado, Adan, van Dam, Rob M, van Klinken, Jan B, Varma, Rohit, Wacher-Rodarte, Niels, Wheeler, Eleanor, Wickremasinghe, Ananda R, van Dijk, Ko Willems, Witte, Daniel R, Yajnik, Chittaranjan S, Yamamoto, Ken, Yamamoto, Kenichi, Yoon, Kyungheon, Yu, Canqing, Yuan, Jian-Min, Yusuf, Salim, Zawistowski, Matthew, Zhang, Liang, Zheng, Wei, VA Million Veteran Program, Raffel, Leslie J, Igase, Michiya, Ipp, Eli, Redline, Susan, Cho, Yoon Shin, Lind, Lars, Province, Michael A, Fornage, Myriam, Hanis, Craig L, Ingelsson, Erik, Zonderman, Alan B, Psaty, Bruce M, Wang, Ya-Xing, Rotimi, Charles N, Becker, Diane M, Matsuda, Fumihiko, Liu, Yongmei, Yokota, Mitsuhiro, Kardia, Sharon LR, Peyser, Patricia A, Pankow, James S, Engert, James C, Bonnefond, Amélie, Froguel, Philippe, Wilson, James G, Sheu, Wayne HH, Wu, Jer-Yuarn, Hayes, M Geoffrey, Ma, Ronald CW, Wong, Tien-Yin, Mook-Kanamori, Dennis O, Tuomi, Tiinamaija, Chandak, Giriraj R, Collins, Francis S, Bharadwaj, Dwaipayan, Paré, Guillaume, Sale, Michèle M, Ahsan, Habibul, Motala, Ayesha A, Shu, Xiao-Ou, Park, Kyong-Soo, Jukema, J Wouter, Cruz, Miguel, Chen, Yii-Der Ida, Rich, Stephen S, McKean-Cowdin, Roberta, Grallert, Harald, Cheng, Ching-Yu, Ghanbari, Mohsen, Tai, E-Shyong, Dupuis, Josee, Kato, Norihiro, Laakso, Markku, Köttgen, Anna, Koh, Woon-Puay, Bowden, Donald W, Palmer, Colin NA, Kooner, Jaspal S, Kooperberg, Charles, Liu, Simin, North, Kari E, Saleheen, Danish, Hansen, Torben, Pedersen, Oluf, Wareham, Nicholas J, Lee, Juyoung, Kim, Bong-Jo, Millwood, Iona Y, Walters, Robin G, Stefansson, Kari, Ahlqvist, Emma, Goodarzi, Mark O, Mohlke, Karen L, Langenberg, Claudia, Haiman, Christopher A, Loos, Ruth JF, Florez, Jose C, Rader, Daniel J, Ritchie, Marylyn D, Zöllner, Sebastian, Mägi, Reedik, Marston, Nicholas A, Ruff, Christian T, van Heel, David A, Finer, Sarah, Denny, Joshua C, Yamauchi, Toshimasa, Kadowaki, Takashi, Chambers, John C, Ng, Maggie CY, Sim, Xueling, Below, Jennifer E, Tsao, Philip S, Chang, Kyong-Mi, McCarthy, Mark I, Meigs, James B, Mahajan, Anubha, Spracklen, Cassandra N, Mercader, Josep M, Boehnke, Michael, Rotter, Jerome I, Vujkovic, Marijana, Voight, Benjamin F, Morris, Andrew P, Zeggini, Eleftheria

مصطلحات موضوعية: Humans, Adipocytes, Chromatin, Coronary Artery Disease, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Disease Progression, Endothelial Cells, Enteroendocrine Cells, Epigenomics, Genetic Predisposition to Disease, Genome-Wide Association Study, Islets of Langerhans, Multifactorial Inheritance, Peripheral Arterial Disease, Single-Cell Analysis

الوصف: Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

وصف الملف: application/pdf; application/zip; text/xml

العلاقة: https://www.repository.cam.ac.uk/handle/1810/366105Test

الإتاحة: https://www.repository.cam.ac.uk/handle/1810/366105Test

المؤلفون: Ahearn, Thomas U, Zhang, Haoyu, Michailidou, Kyriaki, Milne, Roger L, Bolla, Manjeet K, Dennis, Joe, Dunning, Alison M, Lush, Michael, Wang, Qin, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baten, Adinda, Becher, Heiko, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Collée, J Margriet, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Jakimovska, Milena, Jakubowska, Anna, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kauppila, Saila, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kristensen, Vessela N, Krüger, Ute, Kubelka-Sabit, Katerina, Kurian, Allison W, Kyriacou, Kyriacos, Lambrechts, Diether, Lee, Derrick G, Lindblom, Annika, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, McLean, Catriona

المصدر: Breast Cancer Research. 24(1)

مصطلحات موضوعية: Human Genome, Cancer, Genetics, Clinical Research, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Biomarkers, Tumor, Breast Neoplasms, Female, Genome-Wide Association Study, Humans, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Risk, Breast cancer, Etiologic heterogeneity, Genetic predisposition, Common breast cancer susceptibility variants, NBCS Collaborators, ABCTB Investigators, kConFab/AOCS Investigators, Receptor, erbB-2, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: BackgroundGenome-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.MethodsAmong 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.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0dn4070zTest

المؤلفون: Park, Hanla A, Neumeyer, Sonja, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baten, Adinda, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fritschi, Lin, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Han, Sileny, Harkness, Elaine F, Hart, Steven N, He, Wei, Heemskerk-Gerritsen, Bernadette AM, Hopper, John L, Hunter, David J, Jager, Agnes, Jakubowska, Anna, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Koppert, Linetta B, Koutros, Stella, Kristensen, Vessela N, Kurian, Allison W, Lacey, James, Lambrechts, Diether, Le Marchand, Loic, Lo, Wing-Yee, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, Meindl, Alfons, Menon, Usha, Milne, Roger L, Muranen, Taru A, Nevanlinna, Heli

المصدر: British Journal of Cancer. 125(8)

مصطلحات موضوعية: Genetics, Cancer, Substance Misuse, Clinical Research, Human Genome, Prevention, Drug Abuse (NIDA only), Breast Cancer, Tobacco, Tobacco Smoke and Health, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Breast Neoplasms, Case-Control Studies, Cigarette Smoking, Female, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis

الوصف: BackgroundDespite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.MethodsWe applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.ResultsGenetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.ConclusionOur MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/66j3g23qTest

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

المصدر: Genome Medicine. 15

مصطلحات موضوعية: Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study

الوصف: 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 < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-498948Test
https://doi.org/10.1186/s13073-022-01152-5Test
https://uu.diva-portal.org/smash/get/diva2:1745196/FULLTEXT01.pdfTest

المؤلفون: 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, Karoline B. Kuchenbaecker

المصدر: Genome Medicine, Vol 15, Iss 1, Pp 1-18 (2023)

مصطلحات موضوعية: Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study, Medicine, Genetics, QH426-470

الوصف: 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

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1756-994XTest

الوصول الحر: https://doaj.org/article/44abb13c9f464a339579d4ae653343e9Test

المؤلفون: Spracklen, Cassandra N, Horikoshi, Momoko, Kim, Young Jin, Lin, Kuang, Bragg, Fiona, Moon, Sanghoon, Suzuki, Ken, Tam, Claudia HT, Tabara, Yasuharu, Kwak, Soo-Heon, Takeuchi, Fumihiko, Long, Jirong, Lim, Victor JY, Chai, Jin-Fang, Chen, Chien-Hsiun, Nakatochi, Masahiro, Yao, Jie, Choi, Hyeok Sun, Iyengar, Apoorva K, Perrin, Hannah J, Brotman, Sarah M, van de Bunt, Martijn, Gloyn, Anna L, Below, Jennifer E, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Mahajan, Anubha, McCarthy, Mark I, Ng, Maggie CY, Petty, Lauren E, Zhang, Weihua, Morris, Andrew P, Adair, Linda S, Akiyama, Masato, Bian, Zheng, Chan, Juliana CN, Chang, Li-Ching, Chee, Miao-Li, Chen, Yii-Der Ida, Chen, Yuan-Tsong, Chen, Zhengming, Chuang, Lee-Ming, Du, Shufa, Gordon-Larsen, Penny, Gross, Myron, Guo, Xiuqing, Guo, Yu, Han, Sohee, Howard, Annie-Green, Huang, Wei, Hung, Yi-Jen, Hwang, Mi Yeong, Hwu, Chii-Min, Ichihara, Sahoko, Isono, Masato, Jang, Hye-Mi, Jiang, Guozhi, Jonas, Jost B, Kamatani, Yoichiro, Katsuya, Tomohiro, Kawaguchi, Takahisa, Khor, Chiea-Chuen, Kohara, Katsuhiko, Lee, Myung-Shik, Lee, Nanette R, Li, Liming, Liu, Jianjun, Luk, Andrea O, Lv, Jun, Okada, Yukinori, Pereira, Mark A, Sabanayagam, Charumathi, Shi, Jinxiu, Shin, Dong Mun, So, Wing Yee, Takahashi, Atsushi, Tomlinson, Brian, Tsai, Fuu-Jen, van Dam, Rob M, Xiang, Yong-Bing, Yamamoto, Ken, Yamauchi, Toshimasa, Yoon, Kyungheon, Yu, Canqing, Yuan, Jian-Min, Zhang, Liang, Zheng, Wei, Igase, Michiya, Cho, Yoon Shin, Rotter, Jerome I, Wang, Ya-Xing, Sheu, Wayne HH, Yokota, Mitsuhiro, Wu, Jer-Yuarn, Cheng, Ching-Yu, Wong, Tien-Yin, Shu, Xiao-Ou, Kato, Norihiro, Park, Kyong-Soo

المصدر: Nature. 582(7811)

مصطلحات موضوعية: Human Genome, Diabetes, Biotechnology, Genetics, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Aldehyde Dehydrogenase, Mitochondrial, Alleles, Ankyrins, Asian People, Body Mass Index, Case-Control Studies, Diabetes Mellitus, Type 2, Europe, Eye Proteins, Asia, Eastern, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeodomain Proteins, Humans, Male, Nerve Tissue Proteins, RNA, Messenger, Transcription Factors, Transcription, Genetic, General Science & Technology

الوصف: Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6q70w46wTest

المؤلفون: Kapoor, Pooja Middha, Lindström, Sara, Behrens, Sabine, Wang, Xiaoliang, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Dunning, Alison M, Pharoah, Paul DP, Schmidt, Marjanka K, Kraft, Peter, García-Closas, Montserrat, Easton, Douglas F, Milne, Roger L, Chang-Claude, Jenny, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Freeman, Laura E Beane, Beckmann, Matthias W, Benitez, Javier, Bernstein, Leslie, Berrandou, Takiy, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brock, Ian W, Broeks, Annegien, Brooks-Wilson, Angela, Butterbach, Katja, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Carter, Brian D, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Clarke, Christine L, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dai, James Y, Dite, Gillian S, Earp, H Shelton, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, Gaudet, Mia M, Giles, Graham G, González-Neira, Anna, Grundy, Anne, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan E, Harkness, Elaine F, Harstad, Tricia, He, Wei, Heyworth, Jane, Hoover, Robert N, Hopper, John L, Humphreys, Keith, Hunter, David J, Marrón, Pablo Isidro, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Krüger, Ute, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, Makalic, Enes

المصدر: International Journal of Epidemiology. 49(1)

مصطلحات موضوعية: Genetics, Estrogen, Clinical Research, Cancer, Breast Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology, Alleles, Breast Neoplasms, Case-Control Studies, Europe, Factor XIII, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors, White People, Breast Cancer Association Consortium, Europeans, Gene-environment interaction, breast cancer, epidemiology, risk factors, single nucleotide polymorphism, Statistics, Public Health and Health Services, Epidemiology

الوصف: BackgroundPrevious gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions.MethodsAnalyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions.ResultsNoteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10-4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10-5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth.ConclusionsOverall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3zk257dpTest

المؤلفون: Flannick, Jason, Mercader, Josep M, Fuchsberger, Christian, Udler, Miriam S, Mahajan, Anubha, Wessel, Jennifer, Teslovich, Tanya M, Caulkins, Lizz, Koesterer, Ryan, Barajas-Olmos, Francisco, Blackwell, Thomas W, Boerwinkle, Eric, Brody, Jennifer A, Centeno-Cruz, Federico, Chen, Ling, Chen, Siying, Contreras-Cubas, Cecilia, Córdova, Emilio, Correa, Adolfo, Cortes, Maria, DeFronzo, Ralph A, Dolan, Lawrence, Drews, Kimberly L, Elliott, Amanda, Floyd, James S, Gabriel, Stacey, Garay-Sevilla, Maria Eugenia, García-Ortiz, Humberto, Gross, Myron, Han, Sohee, Heard-Costa, Nancy L, Jackson, Anne U, Jørgensen, Marit E, Kang, Hyun Min, Kelsey, Megan, Kim, Bong-Jo, Koistinen, Heikki A, Kuusisto, Johanna, Leader, Joseph B, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Lyssenko, Valeriya, Manning, Alisa K, Marcketta, Anthony, Malacara-Hernandez, Juan Manuel, Martínez-Hernández, Angélica, Matsuo, Karen, Mayer-Davis, Elizabeth, Mendoza-Caamal, Elvia, Mohlke, Karen L, Morrison, Alanna C, Ndungu, Anne, Ng, Maggie CY, O’Dushlaine, Colm, Payne, Anthony J, Pihoker, Catherine, Post, Wendy S, Preuss, Michael, Psaty, Bruce M, Vasan, Ramachandran S, Rayner, N William, Reiner, Alexander P, Revilla-Monsalve, Cristina, Robertson, Neil R, Santoro, Nicola, Schurmann, Claudia, So, Wing Yee, Soberón, Xavier, Stringham, Heather M, Strom, Tim M, Tam, Claudia HT, Thameem, Farook, Tomlinson, Brian, Torres, Jason M, Tracy, Russell P, van Dam, Rob M, Vujkovic, Marijana, Wang, Shuai, Welch, Ryan P, Witte, Daniel R, Wong, Tien-Yin, Atzmon, Gil, Barzilai, Nir, Blangero, John, Bonnycastle, Lori L, Bowden, Donald W, Chambers, John C, Chan, Edmund, Cheng, Ching-Yu, Cho, Yoon Shin, Collins, Francis S, de Vries, Paul S, Duggirala, Ravindranath, Glaser, Benjamin, Gonzalez, Clicerio, Gonzalez, Ma Elena, Groop, Leif, Kooner, Jaspal Singh, Kwak, Soo Heon

المصدر: Nature. 570(7759)

مصطلحات موضوعية: Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Prevention, Biotechnology, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Animals, Case-Control Studies, Decision Support Techniques, Diabetes Mellitus, Type 2, Exome, Female, Gene Frequency, Genome-Wide Association Study, Humans, Male, Mice, Mice, Knockout, Exome Sequencing, Broad Genomics Platform, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES, General Science & Technology

الوصف: Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0zj719b5Test

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

المصدر: essn: 1756-994X ; nlmid: 101475844

مصطلحات موضوعية: Breast cancer susceptibility, Diverse ancestry, Gene regulation, Genome-wide association study, Rare variants, Humans, Female, Breast Neoplasms, Genetic Predisposition to Disease, Black People, Genetic Testing, Polymorphism, Single Nucleotide, Formins

الوصف: 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 < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.

وصف الملف: application/pdf

العلاقة: https://www.repository.cam.ac.uk/handle/1810/346919Test

الإتاحة: https://doi.org/10.17863/CAM.94336Test
https://www.repository.cam.ac.uk/handle/1810/346919Test

المؤلفون: van Zuydam, Natalie R, Ahlqvist, Emma, Sandholm, Niina, Deshmukh, Harshal, Rayner, N William, Abdalla, Moustafa, Ladenvall, Claes, Ziemek, Daniel, Fauman, Eric, Robertson, Neil R, McKeigue, Paul M, Valo, Erkka, Forsblom, Carol, Harjutsalo, Valma, Perna, Annalisa, Rurali, Erica, Marcovecchio, M Loredana, Igo, Robert P, Salem, Rany M, Perico, Norberto, Lajer, Maria, Käräjämäki, Annemari, Imamura, Minako, Kubo, Michiaki, Takahashi, Atsushi, Sim, Xueling, Liu, Jianjun, van Dam, Rob M, Jiang, Guozhi, Tam, Claudia HT, Luk, Andrea OY, Lee, Heung Man, Lim, Cadmon KP, Szeto, Cheuk Chun, So, Wing Yee, Chan, Juliana CN, Ang, Su Fen, Dorajoo, Rajkumar, Wang, Ling, Clara, Tan Si Hua, McKnight, Amy-Jayne, Duffy, Seamus, Pezzolesi, Marcus G, Marre, Michel, Gyorgy, Beata, Hadjadj, Samy, Hiraki, Linda T, Ahluwalia, Tarunveer S, Almgren, Peter, Schulz, Christina-Alexandra, Orho-Melander, Marju, Linneberg, Allan, Christensen, Cramer, Witte, Daniel R, Grarup, Niels, Brandslund, Ivan, Melander, Olle, Paterson, Andrew D, Tregouet, David, Maxwell, Alexander P, Lim, Su Chi, Ma, Ronald CW, Tai, E Shyong, Maeda, Shiro, Lyssenko, Valeriya, Tuomi, Tiinamaija, Krolewski, Andrzej S, Rich, Stephen S, Hirschhorn, Joel N, Florez, Jose C, Dunger, David, Pedersen, Oluf, Hansen, Torben, Rossing, Peter, Remuzzi, Giuseppe, Brosnan, Mary Julia, Palmer, Colin NA, Groop, Per-Henrik, Colhoun, Helen M, Groop, Leif C, McCarthy, Mark I, Koivula, S, Uggeldahl, T, Forslund, T, Halonen, A, Koistinen, A, Koskiaho, P, Laukkanen, M, Saltevo, J, Tiihonen, M, Forsen, M, Granlund, H, Jonsson, A-C, Nyroos, B, Kinnunen, P, Orvola, A, Salonen, T, Vähänen, A, Paldanius, Kotka R, Riihelä, M

المصدر: Diabetes. 67(7)

مصطلحات موضوعية: Diabetes, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Case-Control Studies, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Failure, Chronic, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, Finnish Diabetic Nephropathy Study, Hong Kong Diabetes Registry Theme-based Research Scheme Project Group, Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group, GENIE (GEnetics of Nephropathy an International Effort) Consortium, Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group, SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium, Medical and Health Sciences, Endocrinology & Metabolism

الوصف: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/37m0v97nTest