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1. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Author: Rahmioglu, Nilufer, Mortlock, Sally, Ghiasi, Marzieh, Møller, Peter L., Stefansdottir, Lilja, Galarneau, Geneviève, Turman, Constance, Danning, Rebecca, Law, Matthew H., Sapkota, Yadav, Christofidou, Paraskevi, Skarp, Sini, Giri, Ayush, Banasik, Karina, Krassowski, Michal, Lepamets, Maarja, Marciniak, Błażej, Nõukas, Margit, Perro, Danielle, Sliz, Eeva, Sobalska-Kwapis, Marta, Thorleifsson, Gudmar, Topbas-Selcuki, Nura F., Vitonis, Allison, Westergaard, David, Arnadottir, Ragnheidur, Burgdorf, Kristoffer S., Campbell, Archie, Cheuk, Cecilia S.K., Clementi, Caterina, Cook, James, De Vivo, Immaculata, DiVasta, Amy, Dorien, O., Donoghue, Jacqueline F., Edwards, Todd, Fontanillas, Pierre, Fung, Jenny N., Geirsson, Reynir T., Girling, Jane E., Harkki, Paivi, Harris, Holly R., Healey, Martin, Heikinheimo, Oskari, Holdsworth-Carson, Sarah, Hostettler, Isabel C., Houlden, Henry, Houshdaran, Sahar, Schork, Andrew J., Nyegaard, Mette, Rahmioglu, Nilufer, Mortlock, Sally, Ghiasi, Marzieh, Møller, Peter L., Stefansdottir, Lilja, Galarneau, Geneviève, Turman, Constance, Danning, Rebecca, Law, Matthew H., Sapkota, Yadav, Christofidou, Paraskevi, Skarp, Sini, Giri, Ayush, Banasik, Karina, Krassowski, Michal, Lepamets, Maarja, Marciniak, Błażej, Nõukas, Margit, Perro, Danielle, Sliz, Eeva, Sobalska-Kwapis, Marta, Thorleifsson, Gudmar, Topbas-Selcuki, Nura F., Vitonis, Allison, Westergaard, David, Arnadottir, Ragnheidur, Burgdorf, Kristoffer S., Campbell, Archie, Cheuk, Cecilia S.K., Clementi, Caterina, Cook, James, De Vivo, Immaculata, DiVasta, Amy, Dorien, O., Donoghue, Jacqueline F., Edwards, Todd, Fontanillas, Pierre, Fung, Jenny N., Geirsson, Reynir T., Girling, Jane E., Harkki, Paivi, Harris, Holly R., Healey, Martin, Heikinheimo, Oskari, Holdsworth-Carson, Sarah, Hostettler, Isabel C., Houlden, Henry, Houshdaran, Sahar, Schork, Andrew J., and Nyegaard, Mette
Abstract: Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.
Published: 2023

2. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND Courage-PD [sponsor], Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, Elbaz, Ales, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND Courage-PD [sponsor], Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, and Elbaz, Ales
Abstract: Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly dri
Published: 2023

3. The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

Author: Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, Martin, Richard M, Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, and Martin, Richard M
Abstract: BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activi
Published: 2023
Full Text: View/download PDF

4. The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

Author: Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, Martin, Richard M, Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, and Martin, Richard M
Abstract: BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activi
Published: 2023
Full Text: View/download PDF

5. The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

Author: Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, Martin, Richard M, Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, and Martin, Richard M
Abstract: BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activi
Published: 2023
Full Text: View/download PDF

6. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Author: Rahmioglu, Nilufer, Rahmioglu, Nilufer, Mortlock, Sally, Ghiasi, Marzieh, Møller, Peter L, Stefansdottir, Lilja, Galarneau, Geneviève, Turman, Constance, Danning, Rebecca, Law, Matthew H, Sapkota, Yadav, Christofidou, Paraskevi, Skarp, Sini, Giri, Ayush, Banasik, Karina, Krassowski, Michal, Lepamets, Maarja, Marciniak, Błażej, Nõukas, Margit, Perro, Danielle, Sliz, Eeva, Sobalska-Kwapis, Marta, Thorleifsson, Gudmar, Topbas-Selcuki, Nura F, Vitonis, Allison, Westergaard, David, Arnadottir, Ragnheidur, Burgdorf, Kristoffer S, Campbell, Archie, Cheuk, Cecilia SK, Clementi, Caterina, Cook, James, De Vivo, Immaculata, DiVasta, Amy, Dorien, O, Donoghue, Jacqueline F, Edwards, Todd, Fontanillas, Pierre, Fung, Jenny N, Geirsson, Reynir T, Girling, Jane E, Harkki, Paivi, Harris, Holly R, Healey, Martin, Heikinheimo, Oskari, Holdsworth-Carson, Sarah, Hostettler, Isabel C, Houlden, Henry, Houshdaran, Sahar, Irwin, Juan C, Jarvelin, Marjo-Riitta, Kamatani, Yoichiro, Kennedy, Stephen H, Kepka, Ewa, Kettunen, Johannes, Kubo, Michiaki, Kulig, Bartosz, Kurra, Venla, Laivuori, Hannele, Laufer, Marc R, Lindgren, Cecilia M, MacGregor, Stuart, Mangino, Massimo, Martin, Nicholas G, Matalliotaki, Charoula, Matalliotakis, Michail, Murray, Alison D, Ndungu, Anne, Nezhat, Camran, Olsen, Catherine M, Opoku-Anane, Jessica, Padmanabhan, Sandosh, Paranjpe, Manish, Peters, Maire, Polak, Grzegorz, Porteous, David J, Rabban, Joseph, Rexrode, Kathyrn M, Romanowicz, Hanna, Saare, Merli, Saavalainen, Liisu, Schork, Andrew J, Sen, Sushmita, Shafrir, Amy L, Siewierska-Górska, Anna, Słomka, Marcin, Smith, Blair H, Smolarz, Beata, Szaflik, Tomasz, Szyłło, Krzysztof, Takahashi, Atsushi, Terry, Kathryn L, Tomassetti, Carla, Treloar, Susan A, Vanhie, Arne, Vincent, Katy, Vo, Kim C, Werring, David J, Zeggini, Eleftheria, Zervou, Maria I, DBDS Genomic Consortium, Rahmioglu, Nilufer, Rahmioglu, Nilufer, Mortlock, Sally, Ghiasi, Marzieh, Møller, Peter L, Stefansdottir, Lilja, Galarneau, Geneviève, Turman, Constance, Danning, Rebecca, Law, Matthew H, Sapkota, Yadav, Christofidou, Paraskevi, Skarp, Sini, Giri, Ayush, Banasik, Karina, Krassowski, Michal, Lepamets, Maarja, Marciniak, Błażej, Nõukas, Margit, Perro, Danielle, Sliz, Eeva, Sobalska-Kwapis, Marta, Thorleifsson, Gudmar, Topbas-Selcuki, Nura F, Vitonis, Allison, Westergaard, David, Arnadottir, Ragnheidur, Burgdorf, Kristoffer S, Campbell, Archie, Cheuk, Cecilia SK, Clementi, Caterina, Cook, James, De Vivo, Immaculata, DiVasta, Amy, Dorien, O, Donoghue, Jacqueline F, Edwards, Todd, Fontanillas, Pierre, Fung, Jenny N, Geirsson, Reynir T, Girling, Jane E, Harkki, Paivi, Harris, Holly R, Healey, Martin, Heikinheimo, Oskari, Holdsworth-Carson, Sarah, Hostettler, Isabel C, Houlden, Henry, Houshdaran, Sahar, Irwin, Juan C, Jarvelin, Marjo-Riitta, Kamatani, Yoichiro, Kennedy, Stephen H, Kepka, Ewa, Kettunen, Johannes, Kubo, Michiaki, Kulig, Bartosz, Kurra, Venla, Laivuori, Hannele, Laufer, Marc R, Lindgren, Cecilia M, MacGregor, Stuart, Mangino, Massimo, Martin, Nicholas G, Matalliotaki, Charoula, Matalliotakis, Michail, Murray, Alison D, Ndungu, Anne, Nezhat, Camran, Olsen, Catherine M, Opoku-Anane, Jessica, Padmanabhan, Sandosh, Paranjpe, Manish, Peters, Maire, Polak, Grzegorz, Porteous, David J, Rabban, Joseph, Rexrode, Kathyrn M, Romanowicz, Hanna, Saare, Merli, Saavalainen, Liisu, Schork, Andrew J, Sen, Sushmita, Shafrir, Amy L, Siewierska-Górska, Anna, Słomka, Marcin, Smith, Blair H, Smolarz, Beata, Szaflik, Tomasz, Szyłło, Krzysztof, Takahashi, Atsushi, Terry, Kathryn L, Tomassetti, Carla, Treloar, Susan A, Vanhie, Arne, Vincent, Katy, Vo, Kim C, Werring, David J, Zeggini, Eleftheria, Zervou, Maria I, and DBDS Genomic Consortium
Abstract: Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.
Published: 2023

7. Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

Author: Lindström, Sara, Wang, Lu, Feng, Helian, Majumdar, Arunabha, Huo, Sijia, Macdonald, James, Harrison, Tabitha, Turman, Constance, Chen, Hongjie, Mancuso, Nicholas, Bammler, Theo, Gallinger, Steve, Gruber, Stephen B., Gunter, Marc J., Le Marchand, Loic, Moreno, Victor, Offit, Kenneth, De Vivo, Immaculata, O'Mara, Tracy A., Spurdle, Amanda B., Tomlinson, Ian, Fitzgerald, Rebecca, Gharahkhani, Puya, Gockel, Ines, Jankowski, Janusz, Macgregor, Stuart, Schumacher, Johannes, Barnholtz-Sloan, Jill, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Wrensch, Margaret, Brennan, Paul, Christiani, David C., Johansson, Mattias, Mckay, James, Aldrich, Melinda C., Amos, Christopher I., Landi, Maria Teresa, Tardon, Adonina, Bishop, D Timothy, Demenais, Florence, Goldstein, Alisa M., Iles, Mark M., Kanetsky, Peter A., Law, Matthew H., Amundadottir, Laufey T., Stolzenberg-Solomon, Rachael, Wolpin, Brian M., Klein, Alison, Petersen, Gloria, Risch, Harvey, Chanock, Stephen J., Purdue, Mark P., Scelo, Ghislaine, Pharoah, Paul, Kar, Siddhartha, Hung, Rayjean J., Pasaniuc, Bogdan, Kraft, Peter, Lindström, Sara, Wang, Lu, Feng, Helian, Majumdar, Arunabha, Huo, Sijia, Macdonald, James, Harrison, Tabitha, Turman, Constance, Chen, Hongjie, Mancuso, Nicholas, Bammler, Theo, Gallinger, Steve, Gruber, Stephen B., Gunter, Marc J., Le Marchand, Loic, Moreno, Victor, Offit, Kenneth, De Vivo, Immaculata, O'Mara, Tracy A., Spurdle, Amanda B., Tomlinson, Ian, Fitzgerald, Rebecca, Gharahkhani, Puya, Gockel, Ines, Jankowski, Janusz, Macgregor, Stuart, Schumacher, Johannes, Barnholtz-Sloan, Jill, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Wrensch, Margaret, Brennan, Paul, Christiani, David C., Johansson, Mattias, Mckay, James, Aldrich, Melinda C., Amos, Christopher I., Landi, Maria Teresa, Tardon, Adonina, Bishop, D Timothy, Demenais, Florence, Goldstein, Alisa M., Iles, Mark M., Kanetsky, Peter A., Law, Matthew H., Amundadottir, Laufey T., Stolzenberg-Solomon, Rachael, Wolpin, Brian M., Klein, Alison, Petersen, Gloria, Risch, Harvey, Chanock, Stephen J., Purdue, Mark P., Scelo, Ghislaine, Pharoah, Paul, Kar, Siddhartha, Hung, Rayjean J., Pasaniuc, Bogdan, and Kraft, Peter
Abstract: BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. RESULTS: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. CONCLUSIONS: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
Published: 2023
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8. The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

Author: Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, Martin, Richard M, Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, and Martin, Richard M
Abstract: BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activi
Published: 2023
Full Text: View/download PDF

9. The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

Author: Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, Martin, Richard M, Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, and Martin, Richard M
Abstract: BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activi
Published: 2023
Full Text: View/download PDF

10. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Author: Rahmioglu, Nilufer, Mortlock, Sally, Ghiasi, Marzieh, Møller, Peter L., Stefansdottir, Lilja, Galarneau, Geneviève, Turman, Constance, Danning, Rebecca, Law, Matthew H., Sapkota, Yadav, Christofidou, Paraskevi, Skarp, Sini, Giri, Ayush, Banasik, Karina, Krassowski, Michal, Lepamets, Maarja, Marciniak, Błażej, Nõukas, Margit, Perro, Danielle, Sliz, Eeva, Sobalska-Kwapis, Marta, Thorleifsson, Gudmar, Topbas-Selcuki, Nura F., Vitonis, Allison, Westergaard, David, Arnadottir, Ragnheidur, Burgdorf, Kristoffer S., Campbell, Archie, Cheuk, Cecilia S.K., Clementi, Caterina, Cook, James, De Vivo, Immaculata, DiVasta, Amy, Dorien, O., Donoghue, Jacqueline F., Edwards, Todd, Fontanillas, Pierre, Fung, Jenny N., Geirsson, Reynir T., Girling, Jane E., Harkki, Paivi, Harris, Holly R., Healey, Martin, Heikinheimo, Oskari, Holdsworth-Carson, Sarah, Hostettler, Isabel C., Houlden, Henry, Houshdaran, Sahar, Schork, Andrew J., Nyegaard, Mette, Rahmioglu, Nilufer, Mortlock, Sally, Ghiasi, Marzieh, Møller, Peter L., Stefansdottir, Lilja, Galarneau, Geneviève, Turman, Constance, Danning, Rebecca, Law, Matthew H., Sapkota, Yadav, Christofidou, Paraskevi, Skarp, Sini, Giri, Ayush, Banasik, Karina, Krassowski, Michal, Lepamets, Maarja, Marciniak, Błażej, Nõukas, Margit, Perro, Danielle, Sliz, Eeva, Sobalska-Kwapis, Marta, Thorleifsson, Gudmar, Topbas-Selcuki, Nura F., Vitonis, Allison, Westergaard, David, Arnadottir, Ragnheidur, Burgdorf, Kristoffer S., Campbell, Archie, Cheuk, Cecilia S.K., Clementi, Caterina, Cook, James, De Vivo, Immaculata, DiVasta, Amy, Dorien, O., Donoghue, Jacqueline F., Edwards, Todd, Fontanillas, Pierre, Fung, Jenny N., Geirsson, Reynir T., Girling, Jane E., Harkki, Paivi, Harris, Holly R., Healey, Martin, Heikinheimo, Oskari, Holdsworth-Carson, Sarah, Hostettler, Isabel C., Houlden, Henry, Houshdaran, Sahar, Schork, Andrew J., and Nyegaard, Mette
Abstract: Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.
Published: 2023

11. Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease

Author: Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., Neale, Benjamin M., Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., and Neale, Benjamin M.
Abstract: Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
Published: 2022
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12. Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease

Author: Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., Neale, Benjamin M., Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., and Neale, Benjamin M.
Abstract: Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
Published: 2022
Full Text: View/download PDF

13. Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease

Author: Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., Neale, Benjamin M., Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., and Neale, Benjamin M.
Abstract: Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
Published: 2022
Full Text: View/download PDF

14. Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease

Author: Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., Neale, Benjamin M., Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., and Neale, Benjamin M.
Abstract: Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
Published: 2022
Full Text: View/download PDF

15. Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Author: Ong, Jue Sheng, An, Jiyuan, Han, Xikun, Law, Matthew H., Nandakumar, Priyanka, Schumacher, Johannes, Gockel, Ines, Bohmer, Anne, Jankowski, Janusz, Palles, Claire, Olsen, Catherine M., Neale, Rachel E., Fitzgerald, Rebecca, Thrift, Aaron P., Vaughan, Thomas L., Buas, Matthew, Hinds, David A., Gharahkhani, Puya, Kendall, Bradley J., MacGregor, Stuart, Ong, Jue Sheng, An, Jiyuan, Han, Xikun, Law, Matthew H., Nandakumar, Priyanka, Schumacher, Johannes, Gockel, Ines, Bohmer, Anne, Jankowski, Janusz, Palles, Claire, Olsen, Catherine M., Neale, Rachel E., Fitzgerald, Rebecca, Thrift, Aaron P., Vaughan, Thomas L., Buas, Matthew, Hinds, David A., Gharahkhani, Puya, Kendall, Bradley J., and MacGregor, Stuart
Abstract: Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.
Published: 2022

16. Genetically determined cutaneous nevi and risk of cancer

Author: Dusingize, Jean Claude, Law, Matthew H., Pandeya, Nirmala, Neale, Rachel E., Ong, Jue Sheng, MacGregor, Stuart, Whiteman, David C., Olsen, Catherine M., Dusingize, Jean Claude, Law, Matthew H., Pandeya, Nirmala, Neale, Rachel E., Ong, Jue Sheng, MacGregor, Stuart, Whiteman, David C., and Olsen, Catherine M.
Abstract: Numerous epidemiologic studies have reported positive associations between higher nevus counts and internal cancers. Whether this association represents a true relationship or is due to bias or confounding by factors associated with both nevus counts and cancer remains unclear. We used germline genetic variants for nevus count to test whether this phenotypic trait is a risk-marker for cancer. We calculated polygenic risk scores (PRS) for nevus counts using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 17 427). The association between the nevus PRS and each cancer site was assessed using logistic regression adjusted for the effects of age, sex and the first five principal components. In both cohorts, those in the highest nevus PRS quartile had higher risks of melanoma than those in the lowest quartile (UK Biobank odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.29-1.55; QSkin OR 1.58, 95% CI: 1.29-1.94). We also observed increases in risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with higher nevus PRS quartiles (BCC UK Biobank OR 1.38, 95% CI: 1.33-1.44; QSkin OR 1.20, 95% CI: 1.05-1.38 and SCC UK Biobank OR 1.41, 95% CI: 1.28-1.55; QSkin OR 1.44, 95% CI: 1.19-1.77). We found no consistent evidence that nevus count PRS were associated with risks of developing internal cancers. We infer that associations between nevus counts and internal cancers reported in earlier observational studies arose because of unmeasured confounding or other biases.
Published: 2022

17. Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Author: Ong, Jue-Sheng, An, Jiyuan, Law, Matthew H., Nandakumar, Priyanka, Schumacher, Johannes, Gockel, Ines, Bohmer, Anne, Jankowski, Janusz, Palles, Claire, Olsen, Catherine M., Neale, Rachel E., Fitzgerald, Rebecca, Thrift, Aaron P., Vaughan, Thomas L., Buas, Matthew F., Hinds, David A., Gharahkhani, Puya, Kendall, Bradley J., MacGregor, Stuart, ., 23andMe Research Team, ., Esophageal cancer consortium, Ong, Jue-Sheng, An, Jiyuan, Law, Matthew H., Nandakumar, Priyanka, Schumacher, Johannes, Gockel, Ines, Bohmer, Anne, Jankowski, Janusz, Palles, Claire, Olsen, Catherine M., Neale, Rachel E., Fitzgerald, Rebecca, Thrift, Aaron P., Vaughan, Thomas L., Buas, Matthew F., Hinds, David A., Gharahkhani, Puya, Kendall, Bradley J., MacGregor, Stuart, ., 23andMe Research Team, and ., Esophageal cancer consortium
Abstract: Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.
Published: 2022

18. Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease

Author: Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., Neale, Benjamin M., Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Lall, Kristi, Fave, Marie-Julie, Partanen, Juulia J., Chapman, Sine ad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Munoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J. F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Magi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno, V, Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zollner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., and Neale, Benjamin M.
Abstract: Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
Published: 2022
Full Text: View/download PDF

19. Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Author: Ong, Jue-Sheng, An, Jiyuan, Law, Matthew H., Nandakumar, Priyanka, Schumacher, Johannes, Gockel, Ines, Bohmer, Anne, Jankowski, Janusz, Palles, Claire, Olsen, Catherine M., Neale, Rachel E., Fitzgerald, Rebecca, Thrift, Aaron P., Vaughan, Thomas L., Buas, Matthew F., Hinds, David A., Gharahkhani, Puya, Kendall, Bradley J., MacGregor, Stuart, ., 23andMe Research Team, ., Esophageal cancer consortium, Ong, Jue-Sheng, An, Jiyuan, Law, Matthew H., Nandakumar, Priyanka, Schumacher, Johannes, Gockel, Ines, Bohmer, Anne, Jankowski, Janusz, Palles, Claire, Olsen, Catherine M., Neale, Rachel E., Fitzgerald, Rebecca, Thrift, Aaron P., Vaughan, Thomas L., Buas, Matthew F., Hinds, David A., Gharahkhani, Puya, Kendall, Bradley J., MacGregor, Stuart, ., 23andMe Research Team, and ., Esophageal cancer consortium
Abstract: Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.
Published: 2022

20. Polygenic Risk Scores Stratify Keratinocyte Cancer Risk among Solid Organ Transplant Recipients with Chronic Immunosuppression in a High Ultraviolet Radiation Environment

Author: Seviiri, Mathias, Law, Matthew H, Ong, Jue Sheng, Gharahkhani, Puya, Nyholt, Dale R, Hopkins, Peter, Chambers, Daniel, Campbell, Scott, Isbel, Nicole M, Soyer, H Peter, Olsen, Catherine M, Ellis, Jonathan J, Whiteman, David C, Green, Adele C, MacGregor, Stuart, Seviiri, Mathias, Law, Matthew H, Ong, Jue Sheng, Gharahkhani, Puya, Nyholt, Dale R, Hopkins, Peter, Chambers, Daniel, Campbell, Scott, Isbel, Nicole M, Soyer, H Peter, Olsen, Catherine M, Ellis, Jonathan J, Whiteman, David C, Green, Adele C, and MacGregor, Stuart
Abstract: Solid organ transplant recipients (SOTRs) have elevated risks for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), especially in high UVR environments. We assessed whether polygenic risk scores can improve the prediction of BCC and SCC risks and multiplicity over and above the traditional risk factors in SOTRs in a high UV setting. We built polygenic risk scores for BCC (n = 594,881) and SCC (n = 581,431) using UK Biobank and 23andMe datasets, validated them in the Australian QSkin Sun and Health Study cohort (n > 6,300), and applied them in SOTRs in the skin tumor in allograft recipients cohort from Queensland, Australia, a high UV environment. About half of the SOTRs with a high genetic risk developed BCC (absolute risk = 45.45%, 95% confidence interval = 33.14–58.19%) and SCC (absolute risk = 44.12%, 95% confidence interval = 32.08–56.68%). For both cancers, SOTRs in the top quintile were at >3-fold increased risk relative to those in the bottom quintile. The respective polygenic risk scores improved risk predictions by 2% for BCC (area under the curve = 0.77 vs. 0.75, P = 0.0691) and SCC (area under the curve = 0.84 vs. 0.82, P = 0.0260), over and above the established risk factors, and 19.03% (for BCC) and 18.10% (for SCC) of the SOTRs were reclassified in a high/medium/low risk scenario. The polygenic risk scores also added predictive accuracy for tumor multiplicity (BCC R2 = 0.21 vs. 0.19, P = 3.2 × 10–3; SCC R2 = 0.30 vs. 0.27, P = 4.6 × 10–4).
Published: 2021

21. Polyunsaturated fatty acid levels and the risk of keratinocyte cancer: A Mendelian randomization analysis

Author: Seviiri, Mathias, Law, Matthew H, Ong, Jue-Sheng, Gharahkhani, Puya, Nyholt, Dale R, Olsen, Catherine M, Whiteman, David C, MacGregor, Stuart, Seviiri, Mathias, Law, Matthew H, Ong, Jue-Sheng, Gharahkhani, Puya, Nyholt, Dale R, Olsen, Catherine M, Whiteman, David C, and MacGregor, Stuart
Abstract: Background: Keratinocyte cancer is the commonest cancer, imposing a high economic burden on the health care system. Observational studies have shown mixed associations between polyunsaturated fatty acids (PUFA) and keratinocyte cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We explored whether genetically predicted PUFA levels are associated with BCC and SCC risks. Methods: We conducted a two-sample Mendelian randomization study using PUFA level genome-wide association studies (GWAS) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n > 8,000), and the meta-analysis GWASs from UKB, 23andMe, and Qskin for BCC (n = 651,138) and SCC (n = 635,331) risk. Results: One SD increase in genetically predicted levels of linoleic acid [OR = 0.94, 95% confidence interval (CI) = 0.91–0.97, P = 1.4 × 10–4] and alpha-linolenic acid (OR = 0.91, 95% CI = 0.86–0.96, P = 5.1 × 10–4) was associated with a reduced BCC risk, while arachidonic acid (OR = 1.04, 95% CI = 1.02–1.06, P = 3.2 × 10–4) and eicosapentaenoic acid (OR = 1.10, 95% CI = 1.04–1.16, P = 1.5 × 10–3) were associated with an increased BCC risk. Conclusions: Higher genetically predicted levels of linoleic acid and alpha-linolenic acid were associated with a reduced BCC risk, but arachidonic acid and eicosapentaenoic acid were associated with a higher BCC risk. Impact: PUFA-related diet and supplementation could influence BCC etiology.
Published: 2021

22. Polygenic risk scores allow risk stratification for keratinocyte cancer in organ transplant recipients

Author: Seviiri, Mathias, Law, Matthew H, Ong, Jue Sheng, Gharahkhani, Puya, Nyholt, Dale R, Olsen, Catherine M, Whiteman, David C, MacGregor, Stuart, Seviiri, Mathias, Law, Matthew H, Ong, Jue Sheng, Gharahkhani, Puya, Nyholt, Dale R, Olsen, Catherine M, Whiteman, David C, and MacGregor, Stuart
Abstract: Organ-transplant recipients have an elevated risk of keratinocyte cancers: basal cell carcinoma (BCC) and squamous cell carcinoma. We assessed whether polygenic risk scores (PRSs) generated in nontransplantees from the UK Biobank and 23andMe (13,981 squamous cell carcinoma, 33,736 BCC, and >560,000 controls) can predict keratinocyte cancer risk in an independent organ-transplant recipient cohort. After adjusting for traditional risk factors, compared with the bottom 20%, organ-transplant recipients in the top 20% PRS had an increased risk of BCC (OR = 3.25, 95% confidence interval = 1.44–7.31, P = 4.4 × 10-3) and squamous cell carcinoma (OR = 2.11, 95% confidence interval = 0.98–4.53, P = 0.055). For BCC, the top 20% PRS individuals had an absolute risk of 23%, whereas the risk in the bottom 20% was similar to that in the general nontransplantee population. Adding PRS to a model containing traditional skin cancer risk factors yielded a 3% increase in the area under the curve for receiver operating characteristic curve for BCC (0.73 vs. 0.70); adding the PRS did not significantly increase the area under the curve for receiver operating characteristic curve for squamous cell carcinoma. Organ-transplant recipients in the highest genetic risk quintile could benefit from more intense keratinocyte cancer screening and preventive strategies compared with their counterparts. The BCC PRS improves prediction over and above the traditional skin cancer risk factors by 3%.
Published: 2021

23. Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial

Author: Smit, Amelia K., Allen, Martin, Beswick, Brooke, Butow, Phyllis, Dawkins, Hugh, Dobbinson, Suzanne J., Dunlop, Kate L., Espinoza, David, Fenton, Georgina, Kanetsky, Peter A., Keogh, Louise, Kimlin, Michael G., Kirk, Judy, Law, Matthew H., Lo, Serigne, Low, Cynthia, Mann, Graham J., Reyes-Marcelino, Gillian, Morton, Rachael L., Newson, Ainsley J., Savard, Jacqueline, Trevena, Lyndal, Wordsworth, Sarah, Cust, Anne E., Smit, Amelia K., Allen, Martin, Beswick, Brooke, Butow, Phyllis, Dawkins, Hugh, Dobbinson, Suzanne J., Dunlop, Kate L., Espinoza, David, Fenton, Georgina, Kanetsky, Peter A., Keogh, Louise, Kimlin, Michael G., Kirk, Judy, Law, Matthew H., Lo, Serigne, Low, Cynthia, Mann, Graham J., Reyes-Marcelino, Gillian, Morton, Rachael L., Newson, Ainsley J., Savard, Jacqueline, Trevena, Lyndal, Wordsworth, Sarah, and Cust, Anne E.
Abstract: Purpose: We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes. Methods: In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18–69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline. Results: At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54–0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress. Conclusion: Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm.
Published: 2021

24. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author: Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, other, and, Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, and other, and
Abstract: Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.
Published: 2021

25. Genetically determined risk of keratinocyte carcinoma and risk of other cancers

Author: Dusingize, Jean Claude, Olsen, Catherine M., An, Jiyuan, Pandeya, Nirmala, Liyanage, Upekha E., Law, Matthew H., Neale, Rachel E., Ong, Jue Sheng, Macgregor, Stuart, Whiteman, David C., Dusingize, Jean Claude, Olsen, Catherine M., An, Jiyuan, Pandeya, Nirmala, Liyanage, Upekha E., Law, Matthew H., Neale, Rachel E., Ong, Jue Sheng, Macgregor, Stuart, and Whiteman, David C.
Abstract: Background: Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites. Methods: In the first approach (one-sample), we calculated the polygenic risk scores (PRS) for KC using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-sample) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-Analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants. Results: Using the one-sample approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13-1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-sample approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03-1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort. Conclusion: Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites.
Published: 2021

26. Genomic Risk Score for Melanoma in a Prospective Study of Older Individuals

Author: Bakshi, Andrew, Yan, Mabel, Riaz, Moeen, Polekhina, Galina, Orchard, Suzanne G., Tiller, Jane, Wolfe, Rory, Joshi, Amit, Cao, Yin, McInerney-Leo, Aideen M., Yanes, Tatiane, Janda, Monika, Soyer, H. Peter, Cust, Anne E., Law, Matthew H., Gibbs, Peter, McLean, Catriona, Chan, Andrew T., McNeil, John J., Mar, Victoria J., Lacaze, Paul, Bakshi, Andrew, Yan, Mabel, Riaz, Moeen, Polekhina, Galina, Orchard, Suzanne G., Tiller, Jane, Wolfe, Rory, Joshi, Amit, Cao, Yin, McInerney-Leo, Aideen M., Yanes, Tatiane, Janda, Monika, Soyer, H. Peter, Cust, Anne E., Law, Matthew H., Gibbs, Peter, McLean, Catriona, Chan, Andrew T., McNeil, John J., Mar, Victoria J., and Lacaze, Paul
Abstract: Background: Recent genome-wide association meta-analysis for melanoma doubled the number of previously identified variants. We assessed the performance of an updated polygenic risk score (PRS) in a population of older individuals, where melanoma incidence and cumulative ultraviolet radiation exposure is greatest. Methods: We assessed a PRS for cutaneous melanoma comprising 55 variants in a prospective study of 12 712 individuals in the ASPirin in Reducing Events in the Elderly Trial. We evaluated incident melanomas diagnosed during the trial and prevalent melanomas diagnosed preenrolment (self-reported). Multivariable models examined associations between PRS as a continuous variable (per SD) and categorical (low-risk [0%-20%], medium-risk [21%-80%], high-risk [81%-100%] groups) with incident melanoma. Logistic regression examined the association between PRS and prevalent melanoma. Results: At baseline, mean participant age was 75 years; 55.0% were female, and 528 (4.2%) had prevalent melanomas. During follow-up (median = 4.7 years), 120 (1.0%) incident cutaneous melanomas occurred, 98 of which were in participants with no history. PRS was associated with incident melanoma (hazard ratio = 1.46 per SD, 95% confidence interval [CI] = 1.20 to 1.77) and prevalent melanoma (odds ratio [OR] = 1.55 per SD, 95% CI = 1.42 to 1.69). Participants in the highest-risk PRS group had increased risk compared with the low-risk group for incident melanoma (OR = 2.51, 95% CI = 1.28 to 4.92) and prevalent melanoma (OR = 3.66, 95% CI = 2.69 to 5.05). When stratifying by sex, only males had an association between the PRS and incident melanoma, whereas both sexes had an association between the PRS and prevalent melanoma. Conclusions: A genomic risk score is associated with melanoma risk in older individuals and may contribute to targeted surveillance.
Published: 2021

27. A UVB-responsive common variant at chromosome band 7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor, AHR

Author: Xu, Mai, Mehl, Lindsey, Zhang, Tongwu, Thakur, Rohit, Sowards, Hayley, Myers, Timothy, Jessop, Lea, Chesi, Alessandra, Johnson, Matthew E., Wells, Andrew D., Michael, Helen T., Bunda, Patricia, Jones, Kristine, Higson, Herbert, Hennessey, Rebecca C., Jermusyk, Ashley, Kovacs, Michael A., Landi, Maria Teresa, Iles, Mark M., Goldstein, Alisa M., Choi, Jiyeon, Chanock, Stephen J., Grant, Struan F.A., Chari, Raj, Merlino, Glenn, Law, Matthew H., Brown, Kevin M., other, and, Xu, Mai, Mehl, Lindsey, Zhang, Tongwu, Thakur, Rohit, Sowards, Hayley, Myers, Timothy, Jessop, Lea, Chesi, Alessandra, Johnson, Matthew E., Wells, Andrew D., Michael, Helen T., Bunda, Patricia, Jones, Kristine, Higson, Herbert, Hennessey, Rebecca C., Jermusyk, Ashley, Kovacs, Michael A., Landi, Maria Teresa, Iles, Mark M., Goldstein, Alisa M., Choi, Jiyeon, Chanock, Stephen J., Grant, Struan F.A., Chari, Raj, Merlino, Glenn, Law, Matthew H., Brown, Kevin M., and other, and
Abstract: Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure.
Published: 2021

28. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author: Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice, Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, Lindström, Sara, other, and, Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice, Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, Lindström, Sara, and other, and
Abstract: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
Published: 2021

29. Cell-type-specific meQTLs extend melanoma GWAS annotation beyond eQTLs and inform melanocyte gene-regulatory mechanisms

Author: Zhang, Tongwu, Choi, Jiyeon, Dilshat, Ramile, Einarsdóttir, Berglind Ósk, Kovacs, Michael A., Xu, Mai, Malasky, Michael, Chowdhury, Salma, Jones, Kristine, Bishop, D. Timothy, Goldstein, Alisa M., Iles, Mark M., Landi, Maria Teresa, Law, Matthew H., Shi, Jianxin, Steingrímsson, Eiríkur, Brown, Kevin M., Zhang, Tongwu, Choi, Jiyeon, Dilshat, Ramile, Einarsdóttir, Berglind Ósk, Kovacs, Michael A., Xu, Mai, Malasky, Michael, Chowdhury, Salma, Jones, Kristine, Bishop, D. Timothy, Goldstein, Alisa M., Iles, Mark M., Landi, Maria Teresa, Law, Matthew H., Shi, Jianxin, Steingrímsson, Eiríkur, and Brown, Kevin M.
Abstract: Although expression quantitative trait loci (eQTLs) have been powerful in identifying susceptibility genes from genome-wide association study (GWAS) findings, most trait-associated loci are not explained by eQTLs alone. Alternative QTLs, including DNA methylation QTLs (meQTLs), are emerging, but cell-type-specific meQTLs using cells of disease origin have been lacking. Here, we established an meQTL dataset by using primary melanocytes from 106 individuals and identified 1,497,502 significant cis-meQTLs. Multi-QTL colocalization with meQTLs, eQTLs, and mRNA splice-junction QTLs from the same individuals together with imputed methylome-wide and transcriptome-wide association studies identified candidate susceptibility genes at 63% of melanoma GWAS loci. Among the three molecular QTLs, meQTLs were the single largest contributor. To compare melanocyte meQTLs with those from malignant melanomas, we performed meQTL analysis on skin cutaneous melanomas from The Cancer Genome Atlas (n = 444). A substantial proportion of meQTL probes (45.9%) in primary melanocytes is preserved in melanomas, while a smaller fraction of eQTL genes is preserved (12.7%). Integration of melanocyte multi-QTLs and melanoma meQTLs identified candidate susceptibility genes at 72% of melanoma GWAS loci. Beyond GWAS annotation, meQTL-eQTL colocalization in melanocytes suggested that 841 unique genes potentially share a causal variant with a nearby methylation probe in melanocytes. Finally, melanocyte trans-meQTLs identified a hotspot for rs12203592, a cis-eQTL of a transcription factor, IRF4, with 131 candidate target CpGs. Motif enrichment and IRF4 ChIP-seq analysis demonstrated that these target CpGs are enriched in IRF4 binding sites, suggesting an IRF4-mediated regulatory network. Our study highlights the utility of cell-type-specific meQTLs.
Published: 2021

30. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author: Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, Lindström, Sara, Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, and Lindström, Sara
Abstract: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
Published: 2021
Full Text: View/download PDF

31. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author: Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, Lindström, Sara, Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, and Lindström, Sara
Abstract: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
Published: 2021
Full Text: View/download PDF

32. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author: Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, Lindström, Sara, Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, and Lindström, Sara
Abstract: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
Published: 2021
Full Text: View/download PDF

33. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author: Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, Lindström, Sara, Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, and Lindström, Sara
Abstract: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
Published: 2021
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34. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author: Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, Lindström, Sara, Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice S., Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, and Lindström, Sara
Abstract: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
Published: 2021
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35. Overlapping genetic architecture between Parkinson disease and melanoma

Author: Dube, Umber Ibanez, Laura Budde, John P. Benitez, Bruno A. and Davis, Albert A. Harari, Oscar Iles, Mark M. Law, Matthew H. Brown, Kevin M. Agee, Michelle Alipanahi, Babak and Auton, Adam Bell, Robert K. Bryc, Katarzyna Elson, Sarah L. Fontanillas, Pierre Furlotte, Nicholas A. Hinds, David A. and Huber, Karen E. Kleinman, Aaron Litterman, Nadia K. and McCreight, Jennifer C. McIntyre, Matthew H. Mountain, Joanna L. and Noblin, Elizabeth S. Northover, Carrie A. M. Pitts, Steven J. Sathirapongsasuti, J. Fah Sazonova, Olga V. Shelton, Janie F. Shringarpure, Suyash Tian, Chao Tung, Joyce Y. and Vacic, Vladimir Wilson, Catherine H. Law, M. H. Law, M. H. and Bishop, D. T. Lee, J. E. Brossard, M. Martin, N. G. and Moses, E. K. Song, F. Barrett, J. H. Kumar, R. Easton, D. F. Pharoah, P. D. Swerdlow, A. J. Kypreou, K. P. and Taylor, J. C. Harland, M. Randerson-Moor, J. Akslen, L. A. and Andresen, P. A. Avril, M. F. Azizi, E. Scarra, G. B. and Brown, K. M. Debniak, T. Duffy, D. L. Elder, D. E. Fang, S. Friedman, E. Galan, P. Ghiorzo, P. Gillanders, E. M. and Goldstein, A. M. Gruis, N. A. Hansson, J. Helsing, P. and Hocevar, M. Hoiom, V. Ingvar, C. Kanetsky, P. A. and Chen, W. V. Landi, M. T. Lang, J. Lathrop, G. M. and Lubinski, J. Mackie, R. M. Mann, G. J. Molven, A. and Montgomery, G. W. Novakovic, S. Olsson, H. Puig, S. and Puig-Butille, J. A. Wu, W. Qureshi, A. A. Radford-Smith, G. L. Van der Stoep, N. Van Doorn, R. Whiteman, D. C. and Craig, J. E. Schadendorf, E. Simms, L. A. Burdon, K. P. and Nyholt, D. R. Pooley, K. A. Orr, N. Stratigos, A. J. and Cust, A. E. Ward, S. V. Hayward, N. K. Han, J. Schulze, H. J. Dunning, A. M. Bishop, J. A. Demenais, F. Amos, C. I. MacGregor, S. Iles, M. M. Cruchaga, Carlos 23andMe Research Team Melanoma Meta Analysis Consortium and Dube, Umber Ibanez, Laura Budde, John P. Benitez, Bruno A. and Davis, Albert A. Harari, Oscar Iles, Mark M. Law, Matthew H. Brown, Kevin M. Agee, Michelle Alipanahi, Babak and Auton, Adam Bell, Robert K. Bryc, Katarzyna Elson, Sarah L. Fontanillas, Pierre Furlotte, Nicholas A. Hinds, David A. and Huber, Karen E. Kleinman, Aaron Litterman, Nadia K. and McCreight, Jennifer C. McIntyre, Matthew H. Mountain, Joanna L. and Noblin, Elizabeth S. Northover, Carrie A. M. Pitts, Steven J. Sathirapongsasuti, J. Fah Sazonova, Olga V. Shelton, Janie F. Shringarpure, Suyash Tian, Chao Tung, Joyce Y. and Vacic, Vladimir Wilson, Catherine H. Law, M. H. Law, M. H. and Bishop, D. T. Lee, J. E. Brossard, M. Martin, N. G. and Moses, E. K. Song, F. Barrett, J. H. Kumar, R. Easton, D. F. Pharoah, P. D. Swerdlow, A. J. Kypreou, K. P. and Taylor, J. C. Harland, M. Randerson-Moor, J. Akslen, L. A. and Andresen, P. A. Avril, M. F. Azizi, E. Scarra, G. B. and Brown, K. M. Debniak, T. Duffy, D. L. Elder, D. E. Fang, S. Friedman, E. Galan, P. Ghiorzo, P. Gillanders, E. M. and Goldstein, A. M. Gruis, N. A. Hansson, J. Helsing, P. and Hocevar, M. Hoiom, V. Ingvar, C. Kanetsky, P. A. and Chen, W. V. Landi, M. T. Lang, J. Lathrop, G. M. and Lubinski, J. Mackie, R. M. Mann, G. J. Molven, A. and Montgomery, G. W. Novakovic, S. Olsson, H. Puig, S. and Puig-Butille, J. A. Wu, W. Qureshi, A. A. Radford-Smith, G. L. Van der Stoep, N. Van Doorn, R. Whiteman, D. C. and Craig, J. E. Schadendorf, E. Simms, L. A. Burdon, K. P. and Nyholt, D. R. Pooley, K. A. Orr, N. Stratigos, A. J. and Cust, A. E. Ward, S. V. Hayward, N. K. Han, J. Schulze, H. J. Dunning, A. M. Bishop, J. A. Demenais, F. Amos, C. I. MacGregor, S. Iles, M. M. Cruchaga, Carlos 23andMe Research Team Melanoma Meta Analysis Consortium
Abstract: Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 x 10(-06)) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 x 10(-04)) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.
Published: 2020

36. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, Garcia-Closas, Montserrat, Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, and Garcia-Closas, Montserrat
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence. In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
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37. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, Garcia-Closas, Montserrat, Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, and Garcia-Closas, Montserrat
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence. In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
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38. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, Garcia-Closas, Montserrat, Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, and Garcia-Closas, Montserrat
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence. In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
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39. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Author: Zhang, Yan Dora, Zhang, Yan Dora, Hurson, Amber N, Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F, Milne, Roger L, Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K, Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T, Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B, Casey, Graham, Schmit, Stephanie L, O'Mara, Tracy A, Spurdle, Amanda B, Thompson, Deborah J, Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H, Iles, Mark M, Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D Timothy, Ward, Sarah V, Bondy, Melissa L, Houlston, Richard, Wiencke, John K, Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R, Amos, Christopher I, Hung, Rayjean J, Brennan, Paul, McKay, James, Caporaso, Neil E, Berndt, Sonja I, Birmann, Brenda M, Camp, Nicola J, Kraft, Peter, Rothman, Nathaniel, Slager, Susan L, Berchuck, Andrew, Pharoah, Paul DP, Sellers, Thomas A, Gayther, Simon A, Pearce, Celeste L, Goode, Ellen L, Schildkraut, Joellen M, Moysich, Kirsten B, Amundadottir, Laufey T, Jacobs, Eric J, Klein, Alison P, Petersen, Gloria M, Risch, Harvey A, Stolzenberg-Solomon, Rachel Z, Wolpin, Brian M, Li, Donghui, Eeles, Rosalind A, Haiman, Christopher A, Kote-Jarai, Zsofia, Schumacher, Fredrick R, Al Olama, Ali Amin, Purdue, Mark P, Scelo, Ghislaine, Dalgaard, Marlene D, Greene, Mark H, Grotmol, Tom, Kanetsky, Peter A, McGlynn, Katherine A, Nathanson, Katherine L, Turnbull, Clare, Wiklund, Fredrik, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Zhang, Yan Dora, Zhang, Yan Dora, Hurson, Amber N, Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F, Milne, Roger L, Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K, Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T, Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B, Casey, Graham, Schmit, Stephanie L, O'Mara, Tracy A, Spurdle, Amanda B, Thompson, Deborah J, Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H, Iles, Mark M, Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D Timothy, Ward, Sarah V, Bondy, Melissa L, Houlston, Richard, Wiencke, John K, Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R, Amos, Christopher I, Hung, Rayjean J, Brennan, Paul, McKay, James, Caporaso, Neil E, Berndt, Sonja I, Birmann, Brenda M, Camp, Nicola J, Kraft, Peter, Rothman, Nathaniel, Slager, Susan L, Berchuck, Andrew, Pharoah, Paul DP, Sellers, Thomas A, Gayther, Simon A, Pearce, Celeste L, Goode, Ellen L, Schildkraut, Joellen M, Moysich, Kirsten B, Amundadottir, Laufey T, Jacobs, Eric J, Klein, Alison P, Petersen, Gloria M, Risch, Harvey A, Stolzenberg-Solomon, Rachel Z, Wolpin, Brian M, Li, Donghui, Eeles, Rosalind A, Haiman, Christopher A, Kote-Jarai, Zsofia, Schumacher, Fredrick R, Al Olama, Ali Amin, Purdue, Mark P, Scelo, Ghislaine, Dalgaard, Marlene D, Greene, Mark H, Grotmol, Tom, Kanetsky, Peter A, McGlynn, Katherine A, Nathanson, Katherine L, Turnbull, Clare, Wiklund, Fredrik, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL)
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
Published: 2020

40. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author: Landi, Maria Teresa, Bishop, D. Timothy, MacGregor, Stuart, Machiela, Mitchell J., Stratigos, Alexander J., Ghiorzo, Paola, Brossard, Myriam, Calista, Donato, Choi, Jiyeon, Fargnoli, Maria Concetta, Zhang, Tongwu, Rodolfo, Monica, Trower, Adam J., Menin, Chiara, Martinez, Jacobo, Hadjisavvas, Andreas, Song, Lei, Stefanaki, Irene, Scolyer, Richard, Yang, Rose, Goldstein, Alisa M., Potrony, Miriam, Kypreou, Katerina P., Pastorino, Lorenza, Queirolo, Paola, Pellegrini, Cristina, Cattaneo, Laura, Zawistowski, Matthew, Gimenez-Xavier, Pol, Rodriguez, Arantxa, Elefanti, Lisa, Manoukian, Siranoush, Rivoltini, Licia, Smith, Blair H., Loizidou, Maria A., Del Regno, Laura, Massi, Daniela, Mandala, Mario, Khosrotehrani, Kiarash, Akslen, Lars A., Amos, Christopher I., Andresen, Per A., Avril, Marie Françoise, Azizi, Esther, Soyer, H. Peter, Bataille, Veronique, Dalmasso, Bruna, Bowdler, Lisa M., Burdon, Kathryn P., Chen, Wei V., Codd, Veryan, Craig, Jamie E., Dębniak, Tadeusz, Falchi, Mario, Fang, Shenying, Friedman, Eitan, Simi, Sarah, Galan, Pilar, Garcia-Casado, Zaida, Gillanders, Elizabeth M., Gordon, Scott, Green, Adele, Gruis, Nelleke A., Hansson, Johan, Harland, Mark, Harris, Jessica, Helsing, Per, Henders, Anjali, Hočevar, Marko, Höiom, Veronica, Hunter, David, Ingvar, Christian, Kumar, Rajiv, Lang, Julie, Lathrop, G. Mark, Lee, Jeffrey E., Li, Xin, Lubiński, Jan, Mackie, Rona M., Malt, Maryrose, Malvehy, Josep, McAloney, Kerrie, Mohamdi, Hamida, Molven, Anders, Moses, Eric K., Neale, Rachel E., Novaković, Srdjan, Nyholt, Dale R., Olsson, Håkan, Orr, Nicholas, Fritsche, Lars G., Puig-Butille, Joan Anton, Qureshi, Abrar A., Radford-Smith, Graham L., Randerson-Moor, Juliette, Requena, Celia, Rowe, Casey, Samani, Nilesh J., Sanna, Marianna, Schadendorf, Dirk, Schulze, Hans Joachim, Simms, Lisa A., Smithers, Mark, Song, Fengju, Swerdlow, Anthony J., van der Stoep, Nienke, Kukutsch, Nicole A., Visconti, Alessia, Wallace, Leanne, Ward, Sarah V., Wheeler, Lawrie, Sturm, Richard A., Hutchinson, Amy, Jones, Kristine, Malasky, Michael, Vogt, Aurelie, Zhou, Weiyin, Pooley, Karen A., Elder, David E., Han, Jiali, Hicks, Belynda, Hayward, Nicholas K., Kanetsky, Peter A., Brummett, Chad, Montgomery, Grant W., Olsen, Catherine M., Hayward, Caroline, Dunning, Alison M., Martin, Nicholas G., Evangelou, Evangelos, Mann, Graham J., Long, Georgina, Pharoah, Paul D.P., Easton, Douglas F., Barrett, Jennifer H., Cust, Anne E., Abecasis, Goncalo, Duffy, David L., Whiteman, David C., Gogas, Helen, De Nicolo, Arcangela, Tucker, Margaret A., Newton-Bishop, Julia A., Peris, Ketty, Chanock, Stephen J., Demenais, Florence, Brown, Kevin M., Puig, Susana, Nagore, Eduardo, Shi, Jianxin, Iles, Mark M., Law, Matthew H., other, and, Landi, Maria Teresa, Bishop, D. Timothy, MacGregor, Stuart, Machiela, Mitchell J., Stratigos, Alexander J., Ghiorzo, Paola, Brossard, Myriam, Calista, Donato, Choi, Jiyeon, Fargnoli, Maria Concetta, Zhang, Tongwu, Rodolfo, Monica, Trower, Adam J., Menin, Chiara, Martinez, Jacobo, Hadjisavvas, Andreas, Song, Lei, Stefanaki, Irene, Scolyer, Richard, Yang, Rose, Goldstein, Alisa M., Potrony, Miriam, Kypreou, Katerina P., Pastorino, Lorenza, Queirolo, Paola, Pellegrini, Cristina, Cattaneo, Laura, Zawistowski, Matthew, Gimenez-Xavier, Pol, Rodriguez, Arantxa, Elefanti, Lisa, Manoukian, Siranoush, Rivoltini, Licia, Smith, Blair H., Loizidou, Maria A., Del Regno, Laura, Massi, Daniela, Mandala, Mario, Khosrotehrani, Kiarash, Akslen, Lars A., Amos, Christopher I., Andresen, Per A., Avril, Marie Françoise, Azizi, Esther, Soyer, H. Peter, Bataille, Veronique, Dalmasso, Bruna, Bowdler, Lisa M., Burdon, Kathryn P., Chen, Wei V., Codd, Veryan, Craig, Jamie E., Dębniak, Tadeusz, Falchi, Mario, Fang, Shenying, Friedman, Eitan, Simi, Sarah, Galan, Pilar, Garcia-Casado, Zaida, Gillanders, Elizabeth M., Gordon, Scott, Green, Adele, Gruis, Nelleke A., Hansson, Johan, Harland, Mark, Harris, Jessica, Helsing, Per, Henders, Anjali, Hočevar, Marko, Höiom, Veronica, Hunter, David, Ingvar, Christian, Kumar, Rajiv, Lang, Julie, Lathrop, G. Mark, Lee, Jeffrey E., Li, Xin, Lubiński, Jan, Mackie, Rona M., Malt, Maryrose, Malvehy, Josep, McAloney, Kerrie, Mohamdi, Hamida, Molven, Anders, Moses, Eric K., Neale, Rachel E., Novaković, Srdjan, Nyholt, Dale R., Olsson, Håkan, Orr, Nicholas, Fritsche, Lars G., Puig-Butille, Joan Anton, Qureshi, Abrar A., Radford-Smith, Graham L., Randerson-Moor, Juliette, Requena, Celia, Rowe, Casey, Samani, Nilesh J., Sanna, Marianna, Schadendorf, Dirk, Schulze, Hans Joachim, Simms, Lisa A., Smithers, Mark, Song, Fengju, Swerdlow, Anthony J., van der Stoep, Nienke, Kukutsch, Nicole A., Visconti, Alessia, Wallace, Leanne, Ward, Sarah V., Wheeler, Lawrie, Sturm, Richard A., Hutchinson, Amy, Jones, Kristine, Malasky, Michael, Vogt, Aurelie, Zhou, Weiyin, Pooley, Karen A., Elder, David E., Han, Jiali, Hicks, Belynda, Hayward, Nicholas K., Kanetsky, Peter A., Brummett, Chad, Montgomery, Grant W., Olsen, Catherine M., Hayward, Caroline, Dunning, Alison M., Martin, Nicholas G., Evangelou, Evangelos, Mann, Graham J., Long, Georgina, Pharoah, Paul D.P., Easton, Douglas F., Barrett, Jennifer H., Cust, Anne E., Abecasis, Goncalo, Duffy, David L., Whiteman, David C., Gogas, Helen, De Nicolo, Arcangela, Tucker, Margaret A., Newton-Bishop, Julia A., Peris, Ketty, Chanock, Stephen J., Demenais, Florence, Brown, Kevin M., Puig, Susana, Nagore, Eduardo, Shi, Jianxin, Iles, Mark M., Law, Matthew H., and other, and
Abstract: Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
Published: 2020

41. The emerging field of polygenic risk scores and perspective for use in clinical care

Author: Yanes, Tatiane, McInerney-Leo, Aideen M., Law, Matthew H., Cummings, Shelly, Yanes, Tatiane, McInerney-Leo, Aideen M., Law, Matthew H., and Cummings, Shelly
Abstract: Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes and cancer. Genome-wide association studies (GWAS) have been invaluable in identifying single-nucleotide polymorphisms (SNPs) associated with increased or decreased risk for hundreds of complex disorders. For a given disease, SNPs can be combined to generate a cumulative estimation of risk known as a polygenic risk score (PRS). After years of research, PRSs are increasingly used in clinical settings. In this article, we will review the literature on how both genome-wide and restricted PRSs are developed and the relative merit of each. The validation and evaluation of PRSs will also be discussed, including the recognition that PRS validity is intrinsically linked to the methodological and analytical approach of the foundation GWAS together with the ethnic characteristics of that cohort. Specifically, population differences may affect imputation accuracy, risk magnitude and direction. Even as PRSs are being introduced into clinical practice, there is a push to combine them with clinical and demographic risk factors to develop a holistic disease risk. The existing evidence regarding the clinical utility of PRSs is considered across four different domains: Informing population screening programs, guiding therapeutic interventions, refining risk for families at high risk, and facilitating diagnosis and predicting prognostic outcomes. The evidence for clinical utility in relation to five well-studied disorders is summarized. The potential ethical, legal and social implications are also highlighted.
Published: 2020

42. Overlapping genetic architecture between Parkinson disease and melanoma

Author: Dube, Umber, Ibanez, Laura, Budde, John P., Benitez, Bruno A., Davis, Albert A., Harari, Oscar, Iles, M. M., Law, Matthew H., Brown, Kevin M., Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McCreight, Jennifer C., McIntyre, Matthew H., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A.M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Bishop, D. T., Lee, J. E., Brossard, M., Martin, N. G., Moses, E. K., Song, F., Barrett, J. H., Kumar, R., Easton, D. F., Pharoah, P. D., Swerdlow, A. J., Kypreou, K. P., Taylor, J. C., Harland, M., Randerson-Moor, J., Akslen, L. A., Andresen, P. A., Avril, M. F., Azizi, E., Scarrà, G. B., Brown, K. M., Debniak, T., Duffy, D. L., Elder, D. E., Fang, S., Friedman, E., Galan, P., Ghiorzo, P., Gillanders, E. M., Goldstein, A. M., Gruis, N. A., Hansson, J., Helsing, P., Hočevar, M., Höiom, V., Ingvar, C., Kanetsky, P. A., Chen, W. V., Landi, M. T., Lang, J., Lathrop, G. M., Lubiński, J., Mackie, R. M., Mann, G. J., Molven, A., Montgomery, G. W., Novaković, S., Olsson, H., Puig, S., Puig-Butille, J. A., Wu, W., Qureshi, A. A., Radford-Smith, G. L., van der Stoep, N., van Doorn, R., Whiteman, D. C., Craig, J. E., Schadendorf, E., Simms, L. A., Burdon, K. P., Nyholt, D. R., Pooley, K. A., Orr, N., Stratigos, A. J., Cust, A. E., Ward, S. V., Hayward, N. K., Han, J., Schulze, H. J., Dunning, A. M., Bishop, J. A., Demenais, F., Amos, C. I., MacGregor, S., Cruchaga, Carlos, other, and, Dube, Umber, Ibanez, Laura, Budde, John P., Benitez, Bruno A., Davis, Albert A., Harari, Oscar, Iles, M. M., Law, Matthew H., Brown, Kevin M., Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McCreight, Jennifer C., McIntyre, Matthew H., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A.M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Bishop, D. T., Lee, J. E., Brossard, M., Martin, N. G., Moses, E. K., Song, F., Barrett, J. H., Kumar, R., Easton, D. F., Pharoah, P. D., Swerdlow, A. J., Kypreou, K. P., Taylor, J. C., Harland, M., Randerson-Moor, J., Akslen, L. A., Andresen, P. A., Avril, M. F., Azizi, E., Scarrà, G. B., Brown, K. M., Debniak, T., Duffy, D. L., Elder, D. E., Fang, S., Friedman, E., Galan, P., Ghiorzo, P., Gillanders, E. M., Goldstein, A. M., Gruis, N. A., Hansson, J., Helsing, P., Hočevar, M., Höiom, V., Ingvar, C., Kanetsky, P. A., Chen, W. V., Landi, M. T., Lang, J., Lathrop, G. M., Lubiński, J., Mackie, R. M., Mann, G. J., Molven, A., Montgomery, G. W., Novaković, S., Olsson, H., Puig, S., Puig-Butille, J. A., Wu, W., Qureshi, A. A., Radford-Smith, G. L., van der Stoep, N., van Doorn, R., Whiteman, D. C., Craig, J. E., Schadendorf, E., Simms, L. A., Burdon, K. P., Nyholt, D. R., Pooley, K. A., Orr, N., Stratigos, A. J., Cust, A. E., Ward, S. V., Hayward, N. K., Han, J., Schulze, H. J., Dunning, A. M., Bishop, J. A., Demenais, F., Amos, C. I., MacGregor, S., Cruchaga, Carlos, and other, and
Abstract: Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case–control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10–0.24; P = 4.09 × 10−06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 × 10−04) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.
Published: 2020

43. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Author: Zhang, Yan Dora, Zhang, Yan Dora, Hurson, Amber N, Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F, Milne, Roger L, Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K, Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T, Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B, Casey, Graham, Schmit, Stephanie L, O'Mara, Tracy A, Spurdle, Amanda B, Thompson, Deborah J, Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H, Iles, Mark M, Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D Timothy, Ward, Sarah V, Bondy, Melissa L, Houlston, Richard, Wiencke, John K, Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R, Amos, Christopher I, Hung, Rayjean J, Brennan, Paul, McKay, James, Caporaso, Neil E, Berndt, Sonja I, Birmann, Brenda M, Camp, Nicola J, Kraft, Peter, Rothman, Nathaniel, Slager, Susan L, Berchuck, Andrew, Pharoah, Paul DP, Sellers, Thomas A, Gayther, Simon A, Pearce, Celeste L, Goode, Ellen L, Schildkraut, Joellen M, Moysich, Kirsten B, Amundadottir, Laufey T, Jacobs, Eric J, Klein, Alison P, Petersen, Gloria M, Risch, Harvey A, Stolzenberg-Solomon, Rachel Z, Wolpin, Brian M, Li, Donghui, Eeles, Rosalind A, Haiman, Christopher A, Kote-Jarai, Zsofia, Schumacher, Fredrick R, Al Olama, Ali Amin, Purdue, Mark P, Scelo, Ghislaine, Dalgaard, Marlene D, Greene, Mark H, Grotmol, Tom, Kanetsky, Peter A, McGlynn, Katherine A, Nathanson, Katherine L, Turnbull, Clare, Wiklund, Fredrik, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Zhang, Yan Dora, Zhang, Yan Dora, Hurson, Amber N, Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F, Milne, Roger L, Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K, Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T, Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B, Casey, Graham, Schmit, Stephanie L, O'Mara, Tracy A, Spurdle, Amanda B, Thompson, Deborah J, Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H, Iles, Mark M, Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D Timothy, Ward, Sarah V, Bondy, Melissa L, Houlston, Richard, Wiencke, John K, Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R, Amos, Christopher I, Hung, Rayjean J, Brennan, Paul, McKay, James, Caporaso, Neil E, Berndt, Sonja I, Birmann, Brenda M, Camp, Nicola J, Kraft, Peter, Rothman, Nathaniel, Slager, Susan L, Berchuck, Andrew, Pharoah, Paul DP, Sellers, Thomas A, Gayther, Simon A, Pearce, Celeste L, Goode, Ellen L, Schildkraut, Joellen M, Moysich, Kirsten B, Amundadottir, Laufey T, Jacobs, Eric J, Klein, Alison P, Petersen, Gloria M, Risch, Harvey A, Stolzenberg-Solomon, Rachel Z, Wolpin, Brian M, Li, Donghui, Eeles, Rosalind A, Haiman, Christopher A, Kote-Jarai, Zsofia, Schumacher, Fredrick R, Al Olama, Ali Amin, Purdue, Mark P, Scelo, Ghislaine, Dalgaard, Marlene D, Greene, Mark H, Grotmol, Tom, Kanetsky, Peter A, McGlynn, Katherine A, Nathanson, Katherine L, Turnbull, Clare, Wiklund, Fredrik, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL)
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
Published: 2020

44. Overlapping genetic architecture between Parkinson disease and melanoma.

Author: Dube, Umber, Dube, Umber, Ibanez, Laura, Budde, John P, Benitez, Bruno A, Davis, Albert A, Harari, Oscar, Iles, Mark M, Law, Matthew H, Brown, Kevin M, 23andMe Research Team, Melanoma-Meta-analysis Consortium, Cruchaga, Carlos, Dube, Umber, Dube, Umber, Ibanez, Laura, Budde, John P, Benitez, Bruno A, Davis, Albert A, Harari, Oscar, Iles, Mark M, Law, Matthew H, Brown, Kevin M, 23andMe Research Team, Melanoma-Meta-analysis Consortium, and Cruchaga, Carlos
Abstract: Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 × 10-06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 × 10-04) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.
Published: 2020

45. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, Garcia-Closas, Montserrat, Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, and Garcia-Closas, Montserrat
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence. In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
Full Text: View/download PDF

46. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O’Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D.P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Bishop, David T., Chanock, Stephen J., Chatterjee, Nilanjan, Garcia-Closas, Montserrat, Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O’Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D.P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Bishop, David T., Chanock, Stephen J., Chatterjee, Nilanjan, and Garcia-Closas, Montserrat
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
Published: 2020

47. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author: Landi, Maria Teresa, Bishop, D Timothy, MacGregor, Stuart, Machiela, Mitchell J, Stratigos, Alexander J, Ghiorzo, Paola, Brossard, Myriam, Calista, Donato, Choi, Jiyeon, Fargnoli, Maria Concetta, Zhang, Tongwu, Rodolfo, Monica, Trower, Adam J, Menin, Chiara, Martinez, Jacobo, Hadjisavvas, Andrea, Song, Lei, Stefanaki, Irene, Scolyer, Richard, Yang, Rose, Goldstein, Alisa M, Potrony, Miriam, Kypreou, Katerina P, Pastorino, Lorenza, Queirolo, Paola, Pellegrini, Cristina, Cattaneo, Laura, Zawistowski, Matthew, Gimenez-Xavier, Pol, Rodriguez, Arantxa, Elefanti, Lisa, Manoukian, Siranoush, Rivoltini, Licia, Smith, Blair H, Loizidou, Maria A, Del Regno, Laura, Massi, Daniela, Mandala, Mario, Khosrotehrani, Kiarash, Akslen, Lars A, Amos, Christopher I, Andresen, Per A, Avril, Marie-Françoise, Azizi, Esther, Soyer, H Peter, Bataille, Veronique, Dalmasso, Bruna, Bowdler, Lisa M, Burdon, Kathryn P, Chen, Wei V, Codd, Veryan, Craig, Jamie E, Dębniak, Tadeusz, Falchi, Mario, Fang, Shenying, Friedman, Eitan, Simi, Sarah, Galan, Pilar, Garcia-Casado, Zaida, Gillanders, Elizabeth M, Gordon, Scott, Green, Adele, Gruis, Nelleke A, Hansson, Johan, Harland, Mark, Harris, Jessica, Helsing, Per, Henders, Anjali, Hočevar, Marko, Höiom, Veronica, Hunter, David, Ingvar, Christian, Kumar, Rajiv, Lang, Julie, Lathrop, G Mark, Lee, Jeffrey E, Li, Xin, Lubiński, Jan, Mackie, Rona M, Malt, Maryrose, Malvehy, Josep, McAloney, Kerrie, Mohamdi, Hamida, Molven, Ander, Moses, Eric K, Neale, Rachel E, Novaković, Srdjan, Nyholt, Dale R, Olsson, Håkan, Orr, Nichola, Fritsche, Lars G, Puig-Butille, Joan Anton, Qureshi, Abrar A, Radford-Smith, Graham L, Randerson-Moor, Juliette, Requena, Celia, Rowe, Casey, Samani, Nilesh J, Sanna, Marianna, Schadendorf, Dirk, Schulze, Hans-Joachim, Simms, Lisa A, Smithers, Mark, Song, Fengju, Swerdlow, Anthony J, van der Stoep, Nienke, Kukutsch, Nicole A, Visconti, Alessia, Wallace, Leanne, Ward, Sarah V, Wheeler, Lawrie, Sturm, Richard A, Hutchinson, Amy, Jones, Kristine, Malasky, Michael, Vogt, Aurelie, Zhou, Weiyin, Pooley, Karen A, Elder, David E, Han, Jiali, Hicks, Belynda, Hayward, Nicholas K, Kanetsky, Peter A, Brummett, Chad, Montgomery, Grant W, Olsen, Catherine M, Hayward, Caroline, Dunning, Alison M, Martin, Nicholas G, Evangelou, Evangelo, Mann, Graham J, Long, Georgina, Pharoah, Paul D P, Easton, Douglas F, Barrett, Jennifer H, Cust, Anne E, Abecasis, Goncalo, Duffy, David L, Whiteman, David C, Gogas, Helen, De Nicolo, Arcangela, Tucker, Margaret A, Newton-Bishop, Julia A, Peris, Ketty, Chanock, Stephen J, Demenais, Florence, Brown, Kevin M, Puig, Susana, Nagore, Eduardo, Shi, Jianxin, Iles, Mark M, Law, Matthew H, Peris, Ketty (ORCID:0000-0002-5237-0463), Landi, Maria Teresa, Bishop, D Timothy, MacGregor, Stuart, Machiela, Mitchell J, Stratigos, Alexander J, Ghiorzo, Paola, Brossard, Myriam, Calista, Donato, Choi, Jiyeon, Fargnoli, Maria Concetta, Zhang, Tongwu, Rodolfo, Monica, Trower, Adam J, Menin, Chiara, Martinez, Jacobo, Hadjisavvas, Andrea, Song, Lei, Stefanaki, Irene, Scolyer, Richard, Yang, Rose, Goldstein, Alisa M, Potrony, Miriam, Kypreou, Katerina P, Pastorino, Lorenza, Queirolo, Paola, Pellegrini, Cristina, Cattaneo, Laura, Zawistowski, Matthew, Gimenez-Xavier, Pol, Rodriguez, Arantxa, Elefanti, Lisa, Manoukian, Siranoush, Rivoltini, Licia, Smith, Blair H, Loizidou, Maria A, Del Regno, Laura, Massi, Daniela, Mandala, Mario, Khosrotehrani, Kiarash, Akslen, Lars A, Amos, Christopher I, Andresen, Per A, Avril, Marie-Françoise, Azizi, Esther, Soyer, H Peter, Bataille, Veronique, Dalmasso, Bruna, Bowdler, Lisa M, Burdon, Kathryn P, Chen, Wei V, Codd, Veryan, Craig, Jamie E, Dębniak, Tadeusz, Falchi, Mario, Fang, Shenying, Friedman, Eitan, Simi, Sarah, Galan, Pilar, Garcia-Casado, Zaida, Gillanders, Elizabeth M, Gordon, Scott, Green, Adele, Gruis, Nelleke A, Hansson, Johan, Harland, Mark, Harris, Jessica, Helsing, Per, Henders, Anjali, Hočevar, Marko, Höiom, Veronica, Hunter, David, Ingvar, Christian, Kumar, Rajiv, Lang, Julie, Lathrop, G Mark, Lee, Jeffrey E, Li, Xin, Lubiński, Jan, Mackie, Rona M, Malt, Maryrose, Malvehy, Josep, McAloney, Kerrie, Mohamdi, Hamida, Molven, Ander, Moses, Eric K, Neale, Rachel E, Novaković, Srdjan, Nyholt, Dale R, Olsson, Håkan, Orr, Nichola, Fritsche, Lars G, Puig-Butille, Joan Anton, Qureshi, Abrar A, Radford-Smith, Graham L, Randerson-Moor, Juliette, Requena, Celia, Rowe, Casey, Samani, Nilesh J, Sanna, Marianna, Schadendorf, Dirk, Schulze, Hans-Joachim, Simms, Lisa A, Smithers, Mark, Song, Fengju, Swerdlow, Anthony J, van der Stoep, Nienke, Kukutsch, Nicole A, Visconti, Alessia, Wallace, Leanne, Ward, Sarah V, Wheeler, Lawrie, Sturm, Richard A, Hutchinson, Amy, Jones, Kristine, Malasky, Michael, Vogt, Aurelie, Zhou, Weiyin, Pooley, Karen A, Elder, David E, Han, Jiali, Hicks, Belynda, Hayward, Nicholas K, Kanetsky, Peter A, Brummett, Chad, Montgomery, Grant W, Olsen, Catherine M, Hayward, Caroline, Dunning, Alison M, Martin, Nicholas G, Evangelou, Evangelo, Mann, Graham J, Long, Georgina, Pharoah, Paul D P, Easton, Douglas F, Barrett, Jennifer H, Cust, Anne E, Abecasis, Goncalo, Duffy, David L, Whiteman, David C, Gogas, Helen, De Nicolo, Arcangela, Tucker, Margaret A, Newton-Bishop, Julia A, Peris, Ketty, Chanock, Stephen J, Demenais, Florence, Brown, Kevin M, Puig, Susana, Nagore, Eduardo, Shi, Jianxin, Iles, Mark M, Law, Matthew H, and Peris, Ketty (ORCID:0000-0002-5237-0463)
Abstract: Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10-8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
Published: 2020

48. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, Garcia-Closas, Montserrat, Zhang, Yan Dora, Hurson, Amber N., Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F., Milne, Roger L., Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K., Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T., Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B., Casey, Graham, Schmit, Stephanie L., O'Mara, Tracy A., Spurdle, Amanda B., Thompson, Deborah J., Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H., Iles, Mark M., Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D. Timothy, Ward, Sarah V., Bondy, Melissa L., Houlston, Richard, Wiencke, John K., Melin, Beatrice S., Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R., Amos, Christopher I., Hung, Rayjean J., Brennan, Paul, McKay, James, Caporaso, Neil E., Berndt, Sonja I., Birmann, Brenda M., Camp, Nicola J., Kraft, Peter, Rothman, Nathaniel, Slager, Susan L., Berchuck, Andrew, Pharoah, Paul D. P., Sellers, Thomas A., Gayther, Simon A., Pearce, Celeste L., Goode, Ellen L., Schildkraut, Joellen M., Moysich, Kirsten B., Amundadottir, Laufey T., Jacobs, Eric J., Klein, Alison P., Petersen, Gloria M., Risch, Harvey A., Stolzenberg-Solomon, Rachel Z., Wolpin, Brian M., Li, Donghui, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Al Olama, Ali Amin, Purdue, Mark P., Scelo, Ghislaine, Dalgaard, Marlene D., Greene, Mark H., Grotmol, Tom, Kanetsky, Peter A., McGlynn, Katherine A., Nathanson, Katherine L., Turnbull, Clare, Wiklund, Fredrik, Chanock, Stephen J., Chatterjee, Nilanjan, and Garcia-Closas, Montserrat
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence. In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
Full Text: View/download PDF

49. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways (vol 9, 4774, 2018)

Author: Duffy, David L. Zhu, Gu Li, Xin Sanna, Marianna Iles, Mark M. Jacobs, Leonie C. Evans, David M. Yazar, Seyhan and Beesley, Jonathan Law, Matthew H. Kraft, Peter Visconti, Alessia Taylor, John C. Liu, Fan Wright, Margaret J. and Henders, Anjali K. Bowdler, Lisa Glass, Dan Ikram, M. Arfan and Uitterlinden, Andre G. Madden, Pamela A. Heath, Andrew C. and Nelson, Elliot C. Green, Adele C. Chanock, Stephen and Barrett, Jennifer H. Brown, Matthew A. Hayward, Nicholas K. and MacGregor, Stuart Sturm, Richard A. Hewitt, Alex W. Kayser, Manfred Hunter, David J. Bishop, Julia A. Newton Spector, Timothy D. Montgomery, Grant W. Mackey, David A. Smith, George Davey Nijsten, Tamar E. Bishop, D. Timothy Bataille, Veronique Falchi, Mario Han, Jiali Martin, Nicholas G. and Lee, Jeffrey E. Brossard, Myriam Moses, Eric K. Song, Fengju and Kumar, Rajiv Easton, Douglas F. Pharoah, Paul D. P. and Swerdlow, Anthony J. Kypreou, Katerina P. Harland, Mark and Randerson-Moor, Juliette Akslen, Lars A. Andresen, Per A. and Avril, Marie-Francoise Azizi, Esther Scarra, Giovanna Bianchi and Brown, Kevin M. Debniak, Tadeusz Elder, David E. Fang, Shenying Friedman, Eitan Galan, Pilar Ghiorzo, Paola and Gillanders, Elizabeth M. Goldstein, Alisa M. Gruis, Nelleke A. and Hansson, Johan Helsing, Per Hocevar, Marko Hoiom, Veronica Ingvar, Christian Kanetsky, Peter A. Chen, Wei V. and Landi, Maria Teresa Lang, Julie Lathrop, G. Mark and Lubinski, Jan Mackie, Rona M. Mann, Graham J. Molven, Anders and Novakovic, Srdjan Olsson, Hakan Puig, Susana and Puig-Butille, Joan Anton Radford-Smith, Graham L. van der Stoep, Nienke van Doorn, Remco Whiteman, David C. Craig, Jamie E. and Schadendorf, Dirk Simms, Lisa A. Burdon, Kathryn P. and Nyholt, Dale R. Pooley, Karen A. Orr, Nicholas Stratigos, Alexander J. Cust, Anne E. Ward, Sarah V. Schulze, Hans-Joachim Dunning, Alison M. Demenais, Florence Amos, Christopher I. Melanoma GWAS Consortium and Duffy, David L. Zhu, Gu Li, Xin Sanna, Marianna Iles, Mark M. Jacobs, Leonie C. Evans, David M. Yazar, Seyhan and Beesley, Jonathan Law, Matthew H. Kraft, Peter Visconti, Alessia Taylor, John C. Liu, Fan Wright, Margaret J. and Henders, Anjali K. Bowdler, Lisa Glass, Dan Ikram, M. Arfan and Uitterlinden, Andre G. Madden, Pamela A. Heath, Andrew C. and Nelson, Elliot C. Green, Adele C. Chanock, Stephen and Barrett, Jennifer H. Brown, Matthew A. Hayward, Nicholas K. and MacGregor, Stuart Sturm, Richard A. Hewitt, Alex W. Kayser, Manfred Hunter, David J. Bishop, Julia A. Newton Spector, Timothy D. Montgomery, Grant W. Mackey, David A. Smith, George Davey Nijsten, Tamar E. Bishop, D. Timothy Bataille, Veronique Falchi, Mario Han, Jiali Martin, Nicholas G. and Lee, Jeffrey E. Brossard, Myriam Moses, Eric K. Song, Fengju and Kumar, Rajiv Easton, Douglas F. Pharoah, Paul D. P. and Swerdlow, Anthony J. Kypreou, Katerina P. Harland, Mark and Randerson-Moor, Juliette Akslen, Lars A. Andresen, Per A. and Avril, Marie-Francoise Azizi, Esther Scarra, Giovanna Bianchi and Brown, Kevin M. Debniak, Tadeusz Elder, David E. Fang, Shenying Friedman, Eitan Galan, Pilar Ghiorzo, Paola and Gillanders, Elizabeth M. Goldstein, Alisa M. Gruis, Nelleke A. and Hansson, Johan Helsing, Per Hocevar, Marko Hoiom, Veronica Ingvar, Christian Kanetsky, Peter A. Chen, Wei V. and Landi, Maria Teresa Lang, Julie Lathrop, G. Mark and Lubinski, Jan Mackie, Rona M. Mann, Graham J. Molven, Anders and Novakovic, Srdjan Olsson, Hakan Puig, Susana and Puig-Butille, Joan Anton Radford-Smith, Graham L. van der Stoep, Nienke van Doorn, Remco Whiteman, David C. Craig, Jamie E. and Schadendorf, Dirk Simms, Lisa A. Burdon, Kathryn P. and Nyholt, Dale R. Pooley, Karen A. Orr, Nicholas Stratigos, Alexander J. Cust, Anne E. Ward, Sarah V. Schulze, Hans-Joachim Dunning, Alison M. Demenais, Florence Amos, Christopher I. Melanoma GWAS Consortium
Published: 2019

50. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Author: An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Murray, Liam J., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Whiteman, David C., MacGregor, Stuart, other, and, An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Murray, Liam J., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Whiteman, David C., MacGregor, Stuart, and other, and
Abstract: Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.
Published: 2019

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