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1. 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, Läll, Kristi, Favé, Marie-Julie, Partanen, Juulia J, Chapman, Sinéad 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-Muñoz, 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 JF, 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, Mägi, 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, Zöllner, Sebastian, Biobank Of The Americas, Biobank Japan Project, BioMe, BioVU, CanPath-Ontario Health Study, China Kadoorie Biobank Collaborative Group, Colorado Center For Personalized Medicine, DeCODE Genetics, Estonian Biobank, FinnGen, Generation Scotland, Genes & Health Research Team, LifeLines, Mass General Brigham Biobank, Michigan Genomics Initiative, National Biobank Of Korea, Penn Medicine BioBank, Qatar Biobank, QSkin Sun And Health Study, Taiwan Biobank, HUNT Study, UCLA ATLAS Community Health Initiative, Uganda Genome Resource, UK Biobank, Martin, Alicia R, Willer, Cristen J, Daly, Mark J, Neale, Benjamin M, Namba, Shinichi [0000-0002-7486-3146], Guare, Lindsay A [0000-0001-6988-5319], Palta, Priit [0000-0001-9320-7008], de Bock, Geertruida H [0000-0003-3104-4471], Finer, Sarah [0000-0002-2684-4653], Jansonius, Nomdo M [0000-0002-6495-6568], Rojas-Muñoz, Agustin [0000-0001-7594-0599], Gamazon, Eric R [0000-0003-4204-8734], Ganna, Andrea [0000-0002-8147-240X], Koskela, Jukka T [0000-0002-0154-7222], MacGregor, Stuart [0000-0001-6731-8142], Palotie, Aarno V [0000-0002-2527-5874], and Apollo - University of Cambridge Repository

Subjects
biobank, meta-analysis, genetic association studies, GWAS, ancestry diversity, phenotype harmonization
Abstract

Funder: Biogen, 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
2023
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2. 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

Priyanka Nandakumar, Rebecca C. Fitzgerald, Jue-Sheng Ong, Jiyuan An, Claire Palles, David A. Hinds, Aaron P. Thrift, Catherine M. Olsen, Puya Gharahkhani, Stuart MacGregor, Xikun Han, Ines Gockel, Matthew F. Buas, Janusz Jankowski, Matthew Law, Anne C. Böhmer, Thomas L. Vaughan, Rachel E. Neale, Bradley J. Kendall, Johannes Schumacher, Ong, Jue-Sheng [0000-0002-6062-710X], Thrift, Aaron P [0000-0002-0084-5308], Kendall, Bradley J [0000-0002-6471-2918], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, medicine.medical_specialty, gastro-esophageal reflux disease, Esophageal Neoplasms, Genome-wide association study, Disease, Gastroenterology, Barrett Esophagus, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, genetics, Obesity, Esophagitis, Peptic, Genetic association, business.industry, medicine.disease, humanities, digestive system diseases, Genetic architecture, Barrett's oesophagus, 030104 developmental biology, oesophageal reflux, Multiple comparisons problem, Gastroesophageal Reflux, Etiology, GERD, 030211 gastroenterology & hepatology, business, Body mass index, Genome-Wide Association Study
Abstract

ObjectiveGastro-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.DesignWe 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).ResultsWe 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.ConclusionOur 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
2021

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

Author

Jue-Sheng Ong, René Thieme, Janusz Jankowski, Jiyuan An, Anne C. Böhmer, Stuart MacGregor, David C. Whiteman, Johannes Schumacher, Claire Palles, Rachel E. Neale, Matthew Law, Puya Gharahkhani, Ines Gockel, John Lai, Catherine M. Olsen, Xikun Han, Beacon, Rebecca C. Fitzgerald, Tom L. Vaughan, Gharahkhani, Puya [0000-0002-4203-5952], Law, Matthew H [0000-0002-4303-8821], Ong, Jue-Sheng [0000-0002-6062-710X], Han, Xikun [0000-0002-3823-7308], Olsen, Catherine M [0000-0003-4483-1888], Böhmer, Anne C [0000-0002-5716-786X], Fitzgerald, Rebecca C [0000-0002-3434-3568], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Science, General Physics and Astronomy, Genome-wide association study, Disease, Esophageal Diseases, Genome-wide association studies, Polymorphism, Single Nucleotide, Gastroenterology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Gastro-oesophageal reflux disease, Internal medicine, Humans, Medicine, Genetic Predisposition to Disease, Allele, Esophagus, Risk factor, lcsh:Science, Cancer genetics, Multidisciplinary, business.industry, Esophageal disease, Oesophageal cancer, General Chemistry, medicine.disease, humanities, digestive system diseases, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, 030220 oncology & carcinogenesis, Gastroesophageal Reflux, GERD, Adenocarcinoma, lcsh:Q, Female, business, Genome-Wide Association Study
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., Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.

Published
2019

4. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Author

Gharahkhani, Puya, Jorgenson, Eric, Hysi, Pirro, Khawaja, Anthony P, Pendergrass, Sarah, Han, Xikun, Ong, Jue Sheng, Hewitt, Alex W, Segrè, Ayellet V, Rouhana, John M, Hamel, Andrew R, Igo, Robert P, Choquet, Helene, Qassim, Ayub, Josyula, Navya S, Cooke Bailey, Jessica N, Bonnemaijer, Pieter WM, Iglesias, Adriana, Siggs, Owen M, Young, Terri L, Vitart, Veronique, Thiadens, Alberta AHJ, Karjalainen, Juha, Uebe, Steffen, Melles, Ronald B, Nair, K Saidas, Luben, Robert, Simcoe, Mark, Amersinghe, Nishani, Cree, Angela J, Hohn, Rene, Poplawski, Alicia, Chen, Li Jia, Rong, Shi-Song, Aung, Tin, Vithana, Eranga Nishanthie, NEIGHBORHOOD consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, 23 and Me Research Team, Tamiya, Gen, Shiga, Yukihiro, Yamamoto, Masayuki, Nakazawa, Toru, Currant, Hannah, Birney, Ewan, Wang, Xin, Auton, Adam, Lupton, Michelle K, Martin, Nicholas G, Ashaye, Adeyinka, Olawoye, Olusola, Williams, Susan E, Akafo, Stephen, Ramsay, Michele, Hashimoto, Kazuki, Kamatani, Yoichiro, Akiyama, Masato, Momozawa, Yukihide, Foster, Paul J, Khaw, Peng T, Morgan, James E, Strouthidis, Nicholas G, Kraft, Peter, Kang, Jae H, Pang, Chi Pui, Pasutto, Francesca, Mitchell, Paul, Lotery, Andrew J, Palotie, Aarno, van Duijn, Cornelia, Haines, Jonathan L, Hammond, Chris, Pasquale, Louis R, Klaver, Caroline CW, Hauser, Michael, Khor, Chiea Chuen, Mackey, David A, Kubo, Michiaki, Cheng, Ching-Yu, Craig, Jamie E, MacGregor, Stuart, Wiggs, Janey L, Epidemiology, Ophthalmology, Clinical Genetics, Gharahkhani, Puya [0000-0002-4203-5952], Jorgenson, Eric [0000-0002-5829-8191], Hysi, Pirro [0000-0001-5752-2510], Khawaja, Anthony P [0000-0001-6802-8585], Han, Xikun [0000-0002-3823-7308], Ong, Jue Sheng [0000-0002-6062-710X], Hewitt, Alex W [0000-0002-5123-5999], Rouhana, John M [0000-0002-8599-0271], Igo, Robert P [0000-0002-0024-1993], Choquet, Helene [0000-0001-9839-8667], Josyula, Navya S [0000-0003-2782-8812], Cooke Bailey, Jessica N [0000-0002-4001-8702], Bonnemaijer, Pieter WM [0000-0001-5154-6765], Iglesias, Adriana [0000-0001-5532-764X], Siggs, Owen M [0000-0003-2840-4851], Young, Terri L [0000-0001-6994-9941], Vitart, Veronique [0000-0002-4991-3797], Thiadens, Alberta AHJ [0000-0002-4911-9462], Luben, Robert [0000-0002-5088-6343], Simcoe, Mark [0000-0003-2432-0810], Cree, Angela J [0000-0002-1987-8900], Poplawski, Alicia [0000-0003-2527-0763], Rong, Shi-Song [0000-0001-8352-6363], Vithana, Eranga Nishanthie [0000-0002-8898-0095], Yamamoto, Masayuki [0000-0002-9073-9436], Currant, Hannah [0000-0003-2764-6787], Birney, Ewan [0000-0001-8314-8497], Wang, Xin [0000-0001-7242-357X], Martin, Nicholas G [0000-0003-4069-8020], Olawoye, Olusola [0000-0003-2357-8924], Williams, Susan E [0000-0002-4479-8638], Ramsay, Michele [0000-0002-4156-4801], Kamatani, Yoichiro [0000-0001-8748-5597], Foster, Paul J [0000-0002-4755-177X], Khaw, Peng T [0000-0002-8087-2268], Kraft, Peter [0000-0002-4472-8103], Kang, Jae H [0000-0003-4812-0557], Pasutto, Francesca [0000-0002-0026-5362], Lotery, Andrew J [0000-0001-5541-4305], Haines, Jonathan L [0000-0002-4351-4728], Hammond, Chris [0000-0002-3227-2620], Pasquale, Louis R [0000-0002-5835-3496], Klaver, Caroline CW [0000-0002-2355-5258], Khor, Chiea Chuen [0000-0002-1128-4729], Cheng, Ching-Yu [0000-0003-0655-885X], MacGregor, Stuart [0000-0001-6731-8142], Wiggs, Janey L [0000-0003-1890-3278], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUSLAB, HUS Helsinki and Uusimaa Hospital District, APH - Mental Health, APH - Methodology, and Amsterdam Neuroscience - Neuroinfection & -inflammation

Subjects
0301 basic medicine, Aging, genetic structures, General Physics and Astronomy, Glaucoma, PROTEIN, Genome-wide association study, Neurodegenerative, Genome, ANNOTATION, Genome-wide association studies, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, Polymorphism (computer science), Genotype, 2.1 Biological and endogenous factors, ANZRAG consortium, Aetiology, GENE-EXPRESSION, Genetics, HUMAN-DISEASES, RISK, Multidisciplinary, and Me Research Team, Single Nucleotide, ASSOCIATION, GIGA study group, Biobank Japan project, 3. Good health, PREVALENCE, Open-Angle, Meta-analysis, NEIGHBORHOOD consortium, Optic nerve diseases, Glaucoma, Open-Angle, Asian Continental Ancestry Group, Open angle glaucoma, Science, European Continental Ancestry Group, FinnGen study, Biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, UK Biobank Eye and Vision Consortium, Article, White People, 03 medical and health sciences, Asian People, medicine, Humans, Genetic Predisposition to Disease, 3125 Otorhinolaryngology, ophthalmology, Polymorphism, Eye Disease and Disorders of Vision, Genetic association, MUTATIONS, Human Genome, General Chemistry, medicine.disease, eye diseases, 030104 developmental biology, Genetic Loci, DIFFERENTIAL EXPRESSION ANALYSIS, 030221 ophthalmology & optometry, sense organs, Genome-Wide Association Study
Abstract

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates., Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

Published
2021

5. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author

Fan, Qiao, Pozarickij, Alfred, Tan, Nicholas Y. Q., Guo, Xiaobo, Verhoeven, Virginie J. M., Vitart, Veronique, Guggenheim, Jeremy A., Miyake, Masahiro, Tideman, J. Willem L., Khawaja, Anthony P., Zhang, Liang, MacGregor, Stuart, Höhn, René, Chen, Peng, Biino, Ginevra, Wedenoja, Juho, Saffari, Seyed Ehsan, Tedja, Milly S., Xie, Jing, Lanca, Carla, Wang, Ya Xing, Sahebjada, Srujana, Mazur, Johanna, Mirshahi, Alireza, Martin, Nicholas G., Yazar, Seyhan, Pennell, Craig E., Yap, Maurice, Haarman, Annechien E. G., Enthoven, Clair A., Polling, JanRoelof, Hewitt, Alex W., Jaddoe, Vincent W. V., Van Duijn, Cornelia M., Hayward, Caroline, Polasek, Ozren, Tai, E-Shyong, Yoshikatsu, Hosoda, Hysi, Pirro G., Young, Terri L., Tsujikawa, Akitaka, Wang, Jie Jing, Mitchell, Paul, Pfeiffer, Norbert, Pärssinen, Olavi, Foster, Paul J., Fossarello, Maurizio, Yip, Shea Ping, Williams, Cathy, Hammond, Christopher J., Jonas, Jost B., He, Mingguang, Mackey, David A., Wong, Tien-Yin, Klaver, Caroline C. W., Saw, Seang-Mei, Baird, Paul N., Cheng, Ching-Yu, Bailey-Wilson, Joan E., Veluchamy, Amutha Barathi, Burdon, Kathryn P., Campbell, Harry, Chen, Li Jia, Chew, Emily Y., Craig, Jamie E., Cumberland, Phillippa M., Deangelis, Margaret M., Delcourt, Cécile, Ding, Xiaohu, Evans, David M., Gharahkhani, Puya, Iglesias, Adriana I., Haller, Toomas, Han, Xikun, Hoang, Quan, Igo, Robert P., Iyengar, Sudha K., Kähönen, Mika, Kaprio, Jaakko, Klein, Barbara E., Klein, Ronald, Lass, Jonathan H., Lee, Kris, Lehtimäki, Terho, Lewis, Deyana D., Li, Qing, Li, Shi-Ming, Lyytikäinen, Leo-Pekka, Meguro, Akira, Metspalu, Andres, Middlebrooks, Candace D., Mizuki, Nobuhisa, Musolf, Anthony M., Nickels, Stefan, Oexle, Konrad, Pang, Chi Pui, Paterson, Andrew D., Rahi, Jugnoo S., Raitakari, Olli, Rudan, Igor, Stambolian, Dwight, Simpson, Claire L., Wang, Ningli, Bin Wei, Wen, Williams, Katie M., Wilson, James F., Wojciechowski, Robert, Yamashiro, Kenji, Yam, Jason C. S., Zhou, Xiangtian, Aslam, Tariq, Barman, Sarah A., Barrett, Jenny H., Bishop, Paul, Blows, Peter, Bunce, Catey, Carare, Roxana O., Chakravarthy, Usha, Chan, Michelle, Chua, Sharon Y. L., Crabb, David P., Cumberland, Philippa M., Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew D., Egan, Cathy, Ennis, Sarah, Fruttiger, Marcus, Gallacher, John E. J., Garway-Heath, David F., Gibson, Jane, Gore, Dan, Hardcastle, Alison, Harding, Simon P., Hogg, Ruth E., Keane, Pearse A., Khaw, Sir Peng T., Lascaratos, Gerassimos, Lotery, Andrew J., Macgillivray, Tom, Mackie, Sarah, Martin, Keith, McGaughey, Michelle, McGuinness, Bernadette, McKay, Gareth J., McKibbin, Martin, Mitry, Danny, Moore, Tony, Morgan, James E., Muthy, Zaynah A., O’Sullivan, Eoin, Owen, Chris G., Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Rudnikca, Alicja R., Self, Jay, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Vernon, Stephen A., Viswanathan, Ananth C., Williams, Katie, Woodside, Jayne V., Yates, Max M., Yip, Jennifer, Zheng, Yalin, Verhoeven, Virginie J. M. [0000-0001-7359-7862], Vitart, Veronique [0000-0002-4991-3797], Guggenheim, Jeremy A. [0000-0001-5164-340X], Khawaja, Anthony P. [0000-0001-6802-8585], Zhang, Liang [0000-0001-9264-170X], MacGregor, Stuart [0000-0001-6731-8142], Wedenoja, Juho [0000-0002-6155-0378], Saffari, Seyed Ehsan [0000-0002-6473-4375], Tedja, Milly S. [0000-0003-0356-9684], Lanca, Carla [0000-0001-9918-787X], Wang, Ya Xing [0000-0003-2749-7793], Martin, Nicholas G. [0000-0003-4069-8020], Yap, Maurice [0000-0003-4687-4101], Hewitt, Alex W. [0000-0002-5123-5999], Jaddoe, Vincent W. V. [0000-0003-2939-0041], Hayward, Caroline [0000-0002-9405-9550], Hysi, Pirro G. [0000-0001-5752-2510], Young, Terri L. [0000-0001-6994-9941], Wang, Jie Jing [0000-0001-9491-4898], Pfeiffer, Norbert [0000-0002-5766-2617], Foster, Paul J. [0000-0002-4755-177X], Hammond, Christopher J. [0000-0002-3227-2620], Jonas, Jost B. [0000-0003-2972-5227], Klaver, Caroline C. W. [0000-0002-2355-5258], Baird, Paul N. [0000-0002-1305-3502], and Apollo - University of Cambridge Repository

Subjects
genetic structures, 45, 692/699/3161/3163, 631/208/727/2000, 631/208/205/2138, 45/43, article, sense organs, eye diseases
Abstract

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Published
2021
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6. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Author

Hysi, Pirro G, Choquet, Hélène, Khawaja, Anthony P, Wojciechowski, Robert, Tedja, Milly S, Yin, Jie, Simcoe, Mark J, Patasova, Karina, Mahroo, Omar A, Thai, Khanh K, Cumberland, Phillippa M, Melles, Ronald B, Verhoeven, Virginie JM, Vitart, Veronique, Segre, Ayellet, Stone, Richard A, Wareham, Nicholas, Hewitt, Alex W, Mackey, David A, Klaver, Caroline CW, MacGregor, Stuart, Error, Consortium For Refractive, Khaw, Peng T, Foster, Paul J, Eye, UK, Guggenheim, Jeremy A, 23andMe Inc., Rahi, Jugnoo S, Jorgenson, Eric, Hammond, Christopher J, Apollo-University Of Cambridge Repository, Hysi, Pirro G [0000-0001-5752-2510], Choquet, Hélène [0000-0001-9839-8667], Khawaja, Anthony P [0000-0001-6802-8585], Wojciechowski, Robert [0000-0002-9593-4652], Tedja, Milly S [0000-0003-0356-9684], Simcoe, Mark J [0000-0003-2432-0810], Verhoeven, Virginie JM [0000-0001-7359-7862], Vitart, Veronique [0000-0002-4991-3797], Hewitt, Alex W [0000-0002-5123-5999], Klaver, Caroline CW [0000-0002-2355-5258], MacGregor, Stuart [0000-0001-6731-8142], Khaw, Peng T [0000-0002-8087-2268], Foster, Paul J [0000-0002-4755-177X], Guggenheim, Jeremy A [0000-0001-5164-340X], Jorgenson, Eric [0000-0002-5829-8191], Hammond, Christopher J [0000-0002-3227-2620], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, genetic structures, Consortium for Refractive Error and Myopia, European Continental Ancestry Group, Middle Aged, Refractive Errors, Polymorphism, Single Nucleotide, eye diseases, White People, 23andMe Inc, UK Eye and Vision Consortium, Myopia, Humans, Genetic Predisposition to Disease, Female, Aged, Genome-Wide Association Study
Abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

Published
2021

7. 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, 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, 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., Ong, Jue-Sheng [0000-0002-6062-710X], Dixon-Suen, Suzanne C. [0000-0003-3714-8386], Han, Xikun [0000-0002-3823-7308], Gockel, Ines [0000-0001-7423-713X], Böhmer, Anne [0000-0002-5716-786X], O’Mara, Tracy [0000-0002-5436-3232], Spurdle, Amanda [0000-0003-1337-7897], Law, Matthew H. [0000-0002-4303-8821], Iles, Mark M. [0000-0002-2603-6509], Pharoah, Paul [0000-0001-8494-732X], Zheng, Wei [0000-0003-1226-070X], Thrift, Aaron P. [0000-0002-0084-5308], Olsen, Catherine [0000-0003-4483-1888], Gharahkhani, Puya [0000-0002-4203-5952], Webb, Penelope M. [0000-0003-0733-5930], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
631/67/68, 45/43, article, 692/699/67/2195, 692/4028/67/2324
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
Full Text
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8. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author

Upekha E Liyanage, Amanda B. Spurdle, K. E. Huber, Anna H. Wu, J. Fah Sathirapongsasuti, Douglas A. Corley, C. Tian, Anne Böhmer, David A. Hinds, A. Auton, Xikun Han, Matt Buas, M. Agee, Rebecca C. Fitzgerald, Puya Gharahkhani, Yvonne Romero, S. L. Elson, Ines Gockel, Johannes Schumacher, Leslie Bernstein, Nigel C. Bird, Thomas L. Vaughan, E. S. Noblin, P. Fontanillas, Laura J. Hardie, Brian J. Reid, V. Vacic, M. H. McIntyre, Jiyuan An, Andrew Berchuck, Claire Palles, Weimin Ye, K. Bryc, S. J. Pitts, Jue-Sheng Ong, Geoffrey Liu, R. K. Bell, Rachel E. Neale, Marilie D. Gammon, J. L. Mountain, C. A. M. Northover, Catherine M. Olsen, C. H. Wilson, Janusz Jankowski, Matthew Law, A. Kleinman, Suzanne C. Dixon-Suen, J. Y. Tung, Aaron P. Thrift, Wong-Ho Chow, Paul Pharoah, Jean-Cluade Dusingize, Suyash Shringarpure, Mark M. Iles, Wei Zheng, N. A. Furlotte, Penelope M. Webb, B. Alipanahi, O. V. Sazonova, Stuart MacGregor, David Whiteman, J. F. Shelton, Harvey A. Risch, N. K. Litterman, Tracy A. O'Mara, Nicholas J. Shaheen, Ong, Jue-Sheng [0000-0002-6062-710X], Dixon-Suen, Suzanne C [0000-0003-3714-8386], Han, Xikun [0000-0002-3823-7308], Gockel, Ines [0000-0001-7423-713X], Böhmer, Anne [0000-0002-5716-786X], O'Mara, Tracy [0000-0002-5436-3232], Spurdle, Amanda [0000-0003-1337-7897], Law, Matthew H [0000-0002-4303-8821], Iles, Mark M [0000-0002-2603-6509], Pharoah, Paul [0000-0001-8494-732X], Zheng, Wei [0000-0003-1226-070X], Thrift, Aaron P [0000-0002-0084-5308], Olsen, Catherine [0000-0003-4483-1888], Gharahkhani, Puya [0000-0002-4203-5952], Webb, Penelope M [0000-0003-0733-5930], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Science, General Physics and Astronomy, Sunburn, Single-nucleotide polymorphism, General Biochemistry, Genetics and Molecular Biology, Article, Cancer prevention, 03 medical and health sciences, 0302 clinical medicine, Cancer epidemiology, Risk Factors, Internal medicine, Neoplasms, Mendelian randomization, Vitamin D and neurology, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Risk factor, Vitamin D, Child, Cancer genetics, Multidisciplinary, business.industry, Pigmentation, Case-control study, Cancer, Mendelian Randomization Analysis, General Chemistry, medicine.disease, Confidence interval, 030104 developmental biology, Case-Control Studies, Multivariate Analysis, business
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., Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

Published
2020

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

Author

Montserrat Garcia-Closas, Ellen L. Goode, Mark M. Iles, Brian M. Wolpin, Stephen J. Chanock, Susan L. Slager, Li Hsu, Clare Turnbull, Ccfr, Michael Hoffmeister, Peter T. Campbell, Maria Teresa Landi, Paul D.P. Pharoah, Amber N. Hurson, Melissa L. Bondy, Roger L. Milne, Peter A. Kanetsky, Simon A. Gayther, Christopher A. Haiman, Nicola J. Camp, Mark A. Jenkins, Margaret Wrensch, Bcac, Ulrike Peters, Jill S. Barnholtz-Sloan, Richard S. Houlston, PanScan, Haoyu Zhang, Christopher I. Amos, Ben Kinnersley, GenoMEL, Florence Demenais, Rosalind A. Eeles, Katherine A. McGlynn, Practical, John K. Wiencke, Gicc, Katherine L. Nathanson, Stolzenberg-Solomon R, Brenda M. Birmann, Rayjean J. Hung, Donghui Li, David C. Whiteman, Ghislaine Scelo, Sonja I. Berndt, Alison P. Klein, Sarah V. Ward, Per Hall, D. Timothy Bishop, Tracy A. O'Mara, Kirsten B. Moysich, Corect, Laufey T. Amundadottir, Marjanka K. Schmidt, Ian Tomlinson, Ocac, Yan Zhang, Gloria M. Petersen, Ali Amin Al Olama, Puya Gharahkhani, Deborah J. Thompson, Paul Brennan, Douglas F. Easton, Celeste Leigh Pearce, InterLymph, Jacques Simard, Mark H. Greene, Zsofia Kote-Jarai, Nilanjan Chatterjee, Ecac, Marlene Danner Dalgaard, Mark P. Purdue, Beatrice Melin, Graham Casey, Rajesh Kumar, Jenny Chang-Claude, Thomas A. Sellers, Stephen B. Gruber, Beacon, James D. McKay, Tecac, Stephanie L. Schmit, Tom Grotmol, Kyriaki Michailidou, Immaculata De Vivo, Joellen M. Schildkraut, Eric J. Jacobs, Fredrik Wiklund, Amanda B. Spurdle, Nathaniel Rothman, Parichoy Pal Choudhury, Peter Kraft, Panc, Renal Cancer Gwas, Neil E. Caporaso, Joe Dennis, Matthew Law, Fredrick R. Schumacher, Harvey A. Risch, Stuart MacGregor, Andrew Berchuck, Ilcco, Oral Cancer Gwas, Zhang, Yan Dora [0000-0002-5302-3690], Hurson, Amber N. [0000-0001-7831-6660], Easton, Douglas F. [0000-0003-2444-3247], Milne, Roger L. [0000-0001-5764-7268], Simard, Jacques [0000-0001-6906-3390], Michailidou, Kyriaki [0000-0001-7065-1237], Dennis, Joe [0000-0003-4591-1214], Schmidt, Marjanka K. [0000-0002-2228-429X], Gharahkhani, Puya [0000-0002-4203-5952], Whiteman, David [0000-0003-2563-9559], Jenkins, Mark [0000-0002-8964-6160], Peters, Ulrike [0000-0001-5666-9318], Schmit, Stephanie L. [0000-0001-5931-1194], O’Mara, Tracy A. [0000-0002-5436-3232], Spurdle, Amanda B. [0000-0003-1337-7897], Thompson, Deborah J. [0000-0003-1465-5799], Tomlinson, Ian [0000-0003-3037-1470], Landi, Maria Teresa [0000-0003-4507-329X], Law, Matthew H. [0000-0002-4303-8821], Iles, Mark M. [0000-0002-2603-6509], Demenais, Florence [0000-0001-8361-0936], Kumar, Rajiv [0000-0002-6093-0395], MacGregor, Stuart [0000-0001-6731-8142], Bishop, D. Timothy [0000-0002-8752-8785], Houlston, Richard [0000-0002-5268-0242], Barnholtz-Sloan, Jill [0000-0001-6190-9304], Kinnersley, Ben [0000-0003-1783-6296], Amos, Christopher I. [0000-0002-8540-7023], Hung, Rayjean J. [0000-0002-4486-7496], Brennan, Paul [0000-0002-0518-8714], Birmann, Brenda M. [0000-0002-7550-5498], Camp, Nicola J. [0000-0002-4788-1998], Kraft, Peter [0000-0002-4472-8103], Pharoah, Paul D. P. [0000-0001-8494-732X], Gayther, Simon A. [0000-0001-7937-5443], Amundadottir, Laufey T. [0000-0003-1859-8971], Jacobs, Eric J. [0000-0002-8458-7659], Klein, Alison P. [0000-0003-2737-8399], Eeles, Rosalind A. [0000-0002-3698-6241], Schumacher, Fredrick R. [0000-0002-3073-7463], Greene, Mark H. [0000-0003-1852-9239], Kanetsky, Peter A. [0000-0002-5567-9618], Nathanson, Katherine L. [0000-0002-6740-0901], Wiklund, Fredrik [0000-0002-4623-0544], Chanock, Stephen J. [0000-0002-2324-3393], Garcia-Closas, Montserrat [0000-0003-1033-2650], Apollo - University of Cambridge Repository, Hurson, Amber N [0000-0001-7831-6660], Easton, Douglas F [0000-0003-2444-3247], Milne, Roger L [0000-0001-5764-7268], Schmidt, Marjanka K [0000-0002-2228-429X], Schmit, Stephanie L [0000-0001-5931-1194], O'Mara, Tracy A [0000-0002-5436-3232], Spurdle, Amanda B [0000-0003-1337-7897], Thompson, Deborah J [0000-0003-1465-5799], Law, Matthew H [0000-0002-4303-8821], Iles, Mark M [0000-0002-2603-6509], Bishop, D Timothy [0000-0002-8752-8785], Amos, Christopher I [0000-0002-8540-7023], Hung, Rayjean J [0000-0002-4486-7496], Birmann, Brenda M [0000-0002-7550-5498], Camp, Nicola J [0000-0002-4788-1998], Pharoah, Paul DP [0000-0001-8494-732X], Gayther, Simon A [0000-0001-7937-5443], Amundadottir, Laufey T [0000-0003-1859-8971], Jacobs, Eric J [0000-0002-8458-7659], Klein, Alison P [0000-0003-2737-8399], Eeles, Rosalind A [0000-0002-3698-6241], Schumacher, Fredrick R [0000-0002-3073-7463], Greene, Mark H [0000-0003-1852-9239], Kanetsky, Peter A [0000-0002-5567-9618], Nathanson, Katherine L [0000-0002-6740-0901], and Chanock, Stephen J [0000-0002-2324-3393]

Subjects
Male, 0301 basic medicine, Oncology, Multifactorial Inheritance, 45/43, General Physics and Astronomy, Diseases, Genome-wide association study, 0302 clinical medicine, Risk Factors, Neoplasms, 631/208/68, lcsh:Science, Cancer genetics, Multidisciplinary, 692/699, Incidence, article, 030220 oncology & carcinogenesis, Medical genetics, Female, Medical Genetics, medicine.medical_specialty, Science, Biology, Polymorphism, Single Nucleotide, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, Animals, Humans, Genetic Predisposition to Disease, Lung cancer, Genetic association, Medicinsk genetik, Cancer och onkologi, Models, Genetic, 45, Cancer, General Chemistry, Heritability, medicine.disease, 030104 developmental biology, Sample size determination, Relative risk, Cancer and Oncology, lcsh:Q, Ovarian cancer, Genome-Wide Association Study
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

10. Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Author

Bonnemaijer, Pieter WM, van Leeuwen, Elisabeth M, Iglesias, Adriana I, Gharahkhani, Puya, Vitart, Veronique, Khawaja, Anthony P, Simcoe, Mark, Hoehn, Rene, Cree, Angela J, Igo, Rob P, Burdon, Kathryn P, Craig, Jamie E, Hewitt, Alex W, Jonas, Jost, Khor, Chiea-Cheun, Pasutto, Francesca, Mackey, David A, Mitchell, Paul, Mishra, Aniket, Pang, Calvin, Pasquale, Louis R, Springelkamp, Henriette, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Viswanathan, Ananth C, Wojciechowski, Robert, Wong, Tien, Young, Terrri L, Zeller, Tanja, Atan, Denize, Aslam, Tariq, Barman, Sarah A, Barrett, Jenny H, Bishop, Paul, Blows, Peter, Bunce, Catey, Carare, Roxana O, Chakravarthy, Usha, Chan, Michelle, Chua, Sharon YL, Crabb, David P, Cumberland, Philippa M, Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew D, Egan, Cathy, Ennis, Sarah, Foster, Paul, Fruttiger, Marcus, Gallacher, John EJ, Garway, David F, Gibson, Jane, Gore, Dan, Guggenheim, Jeremy A, Hardcastle, Alison, Harding, Simon P, Hogg, Ruth E, Keane, Pearse A, Khaw, Peng T, Lascaratos, Gerassimos, Macgillivray, Tom, Mackie, Sarah, Martin, Keith, McGaughey, Michelle, McGuinness, Bernadette, Mckay, Gareth J, McKibbin, Martin, Mitry, Danny, Moore, Tony, Morgan, James E, Muthy, Zaynah A, O'Sullivan, Eoin, Owen, Chris G, Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Rahi, Jugnoo S, Rudnikca, Alicja R, Self, Jay, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Vernon, Stephen A, Williams, Cathy, Williams, Katie, Woodside, Jayne V, Yates, Max M, Yip, Jennifer, Zheng, Yalin, Allingham, Rand, Budenz, Don, Bailey, Jessica Cooke, Fingert, John, Gaasterland, Douglas, Gaasterland, Teresa, Haines, Jonathan L, Hark, Lisa, Hauser, Michael, Kang, Jae Hee, Kraft, Peter, Lee, Richard, Lichter, Paul, Liu, Yutao, Moroi, Syoko, Pericak, Margaret, Realini, Anthony, Rhee, Doug, Richards, Julia R, Ritch, Robert, Scott, William K, Singh, Kuldev, Sit, Arthur, Vollrath, Douglas, Weinreb, Robert, Wollstein, Gadi, Wilmer, Don Zack, Gerhold-Ay, Aslihan, Nickels, Stefan, Wilson, James F, Hayward, Caroline, Boutin, Thibaud S, Polasek, Ozren, Aung, Tin, Khor, Chiea Chuen, Amin, Najaf, Lotery, Andrew J, Wiggs, Janey L, Cheng, Ching-Yu, Hysi, Pirro G, Hammond, Christopher J, Thiadens, Alberta AHJ, MacGregor, Stuart, Klaver, Caroline CW, van Duijn, Cornelia M, Consortium, Int Glaucoma Genetics, Consortium, Uk Biobank Eye Vision, Consortium, NEIGHBORHOOD, Epidemiology, Ophthalmology, Clinical Genetics, Bonnemaijer, Pieter WM [0000-0001-5154-6765], Iglesias, Adriana I [0000-0001-5532-764X], Gharahkhani, Puya [0000-0002-4203-5952], Vitart, Veronique [0000-0002-4991-3797], Khawaja, Anthony P [0000-0001-6802-8585], Simcoe, Mark [0000-0003-2432-0810], Nickels, Stefan [0000-0003-0415-2354], Wilson, James F [0000-0001-5751-9178], Hayward, Caroline [0000-0002-9405-9550], Boutin, Thibaud S [0000-0003-4754-1675], Khor, Chiea Chuen [0000-0002-1128-4729], Lotery, Andrew J [0000-0001-5541-4305], Wiggs, Janey L [0000-0003-1890-3278], Cheng, Ching-Yu [0000-0003-0655-885X], Hysi, Pirro G [0000-0001-5752-2510], Hammond, Christopher J [0000-0002-3227-2620], MacGregor, Stuart [0000-0001-6731-8142], Klaver, Caroline CW [0000-0002-2355-5258], and Apollo - University of Cambridge Repository

Subjects
genetic structures, Optic disk, Medicine (miscellaneous), Genome-wide association study, Neurodegenerative, Genome-wide association studies, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, Optic Nerve Diseases, 2.1 Biological and endogenous factors, Aetiology, 610 Medicine & health, lcsh:QH301-705.5, 0303 health sciences, Agricultural and Biological Sciences(all), Single Nucleotide, medicine.anatomical_structure, NEIGHBORHOOD consortium, General Agricultural and Biological Sciences, Optic disc, Signal Transduction, Optic Disk, Quantitative Trait Loci, International Glaucoma Genetics Consortium, Quantitative trait locus, Biology, Genetic correlation, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, UK Biobank Eye and Vision Consortium, 03 medical and health sciences, Quantitative Trait, Quantitative Trait, Heritable, medicine, Genetics, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Polymorphism, Heritable, Eye Disease and Disorders of Vision, Genetic Association Studies, 030304 developmental biology, Genetic association, CENTRAL CORNEAL THICKNESS, METAANALYSIS, GLAUCOMA, EXPRESSION, HERITABILITY, PREVALENCE, STATISTICS, PANEL, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, Haplotype, Human Genome, Computational Biology, Glaucoma, Molecular Sequence Annotation, eye diseases, lcsh:Biology (General), Evolutionary biology, Case-Control Studies, RE, sense organs, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH., The International Glaucoma Genetics Consortium reports a genome-wide association study meta-analysis of optic disc parameters relevant to primary open-angle glaucoma. They identify two novel variants in PPP1R36-PLEKHG3 and SERPINE3 by multi-trait analysis in European-ancestry cohorts that were replicated in independent Asian cohorts.

Published
2019

11. 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., Gockel, Ines, Thieme, René, Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Whiteman, David C., MacGregor, Stuart, 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., Gharahkhani, Puya [0000-0002-4203-5952], Law, Matthew H. [0000-0002-4303-8821], Ong, Jue-Sheng [0000-0002-6062-710X], Han, Xikun [0000-0002-3823-7308], Olsen, Catherine M. [0000-0003-4483-1888], Böhmer, Anne C. [0000-0002-5716-786X], Fitzgerald, Rebecca C. [0000-0002-3434-3568], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
631/67/1504/1477, 631/208/205/2138, 45/43, article, 38/39, 631/208/68, 692/699/1503/1476/196, health care economics and organizations, humanities, digestive system diseases
Abstract

Funder: The Swedish Esophageal Cancer Study was funded by grants (R01 CA57947-03) from the National Cancer Institute he California Tobacco Related Research Program (3RT-0122; and; 10RT-0251) Marit Peterson Fund for Melanoma Research. CIDR is supported by contract HHSN268200782096C, 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

12. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author

Nicholas G. Martin, René Höhn, Paul Mitchell, Gavin Band, Pamela Whittaker, Michelle Ricketts, Pirro G. Hysi, Jenefer M. Blackwell, Grant W. Montgomery, Elena Rochtchina, Manfred E. Beutel, Richard A. Mills, Anna Rautanen, Alagurevathi Jayakumar, Colin Freeman, Stephen Sawcer, Stuart MacGregor, Irene Schmidtmann, Cornelia M. van Duijn, Nicholas W. Wood, Sayoko E. Moroi, Jonathan L. Haines, Aniket Mishra, Ananth C. Viswanathan, Jie Jin Wang, Donald L. Budenz, Seyhan Yazar, Janey L. Wiggs, Garrett Hellenthal, Kathryn P. Burdon, Jerome I. Rotter, Jamie E Craig, Puya Gharahkhani, Juan P. Casas, R. Rand Allingham, Jost B. Jonas, Ozren Polasek, Julia E. Richards, Sarah Edkins, Rodney J. Scott, Abhishek Nag, Tanja Zeller, Rhian Gwilliam, Chris C. A. Spencer, David S. Friedman, Adriana I Iglesias, Radhi Ravindrarajah, Kent D. Taylor, Caroline Hayward, Eleni Giannoulatou, David A. Mackey, Michael A. Hauser, Paul J. Foster, Emma Gray, Audrey Duncanson, Yih Chung Tham, Murray H. Brilliant, Ching-Yu Cheng, William K. Scott, Robert N. Weinreb, Hugh S. Markus, Xueling Sim, David S. Siscovick, Matti Pirinen, John H. Fingert, Yelena Bykhovskaya, Louis R. Pasquale, Peter Donnelly, Donald J. Zack, Kuldev Singh, Cordelia Langford, Zhan Su, Céline Bellenguez, Joel S. Schuman, Peter Kraft, Christopher G. Mathew, Hannah Blackburn, Sara Widaa, Yuan Shi, Gabriel Cuellar-Partida, André G. Uitterlinden, Naomi Hammond, Panos Deloukas, Richard K. Lee, Robert Plomin, Jessica N. Cooke Bailey, Jae H. Kang, John Attia, Yutao Liu, Simon C. Potter, Jennifer Liddle, Matthew Gillman, Alex W. Hewitt, Margaret A. Pericak-Vance, James F. Wilson, Tien Yin Wong, Elvira Bramon, Janusz Jankowski, Henriët Springelkamp, Sarah E. Hunt, Anthony P Khawaja, Veronique Vitart, Xiaohui Li, Pieter W.M. Bonnemaijer, Damjan Vukcevic, Paul R. Lichter, Aiden Corvin, Sionne E. M. Lucas, Matthew Waller, Caroline C W Klaver, Douglas E. Gaasterland, Terry Gaasterland, Norbert Pfeiffer, Douglas Vollrath, Anthony Realini, Eranga N. Vithana, Gadi Wollstein, Thibaud Boutin, Owen T. McCann, Paul A. Weston, Lisa S. Kearns, Inês Barroso, Richard G. Pearson, Christopher J Hammond, Colin N. A. Palmer, Michael Inouye, Chiea Chuen Khor, Stephanie Loomis, Sandra E Staffieri, Yaron S. Rabinowitz, Richard C. Trembath, Tin Aung, William G. Christen, Paul N. Baird, Jing Xie, Elisabeth M. van Leeuwen, Serge Dronov, Arthur J. Sit, Colin E. Willoughby, Kang Zhang, Matthew A. Brown, Suzannah Bumpstead, Amy Strange, Elizabeth G. Holliday, Clinical Genetics, Epidemiology, Ophthalmology, Internal Medicine, Experimental Immunology, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Iglesias, Adriana I [0000-0001-5532-764X], Gharahkhani, Puya [0000-0002-4203-5952], Bailey, Jessica N Cooke [0000-0002-4001-8702], Li, Xiaohui [0000-0002-5037-3572], Khawaja, Anthony P [0000-0001-6802-8585], Haines, Jonathan L [0000-0002-4351-4728], Hayward, Caroline [0000-0002-9405-9550], Bonnemaijer, Pieter [0000-0001-5154-6765], Staffieri, Sandra E [0000-0003-3131-9359], Jonas, Jost B [0000-0003-2972-5227], Kang, Jae H [0000-0003-4812-0557], Wilson, James F [0000-0001-5751-9178], Foster, Paul J [0000-0002-4755-177X], Hysi, Pirro G [0000-0001-5752-2510], Hewitt, Alex W [0000-0002-5123-5999], Khor, Chiea Chuen [0000-0002-1128-4729], Pasquale, Louis R [0000-0002-5835-3496], Montgomery, Grant W [0000-0002-4140-8139], Klaver, Caroline CW [0000-0002-2355-5258], Hammond, Christopher J [0000-0002-3227-2620], Wiggs, Janey L [0000-0003-1890-3278], Burdon, Kathryn P [0000-0001-8217-1249], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Lumican, Candidate gene, genetic structures, Fibrillin-1, Gene Expression, General Physics and Astronomy, Glaucoma, Genome-wide association study, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, 0302 clinical medicine, Myopia, lcsh:Science, Corneal Dystrophies, Hereditary, Genetics, Multidisciplinary, Eye Diseases, Hereditary, Mendelian Randomization Analysis, 3. Good health, medicine.anatomical_structure, Proteoglycans, Decorin, Glaucoma, Open-Angle, Keratoconus, Science, Quantitative Trait Loci, 610 Medicine & health, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, White People, General Biochemistry, Genetics and Molecular Biology, Transforming Growth Factor beta2, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Quantitative Trait, Heritable, Asian People, medicine, Humans, CHROMATIN STATES, GENE-EXPRESSION, RISK-FACTOR, MUTATIONS, LUMICAN, MOUSE, KERATOCONUS, DECORIN, POLYMORPHISMS, HERITABILITY, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Loeys-Dietz Syndrome, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genome, Human, General Chemistry, medicine.disease, eye diseases, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030221 ophthalmology & optometry, lcsh:Q, Ehlers-Danlos Syndrome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, Genome-Wide Association Study
Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Published
2018

13. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Author

Justice, Anne E, Karaderi, Tugce, Highland, Heather M, Young, Kristin L, Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L, Fine, Rebecca S, Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W, Locke, Adam E, Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Angelantonio, Emanuele Di, Dörr, Marcus, Drenos, Fotios, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Fornage, Myriam, Fox, Caroline S, Franks, Paul W, Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T, Hayward, Caroline, Heid, Iris M, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jarvik, Gail P, Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M, Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kovacs, Peter, Krämer, Bernhard K, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas GD, McCarthy, Mark I, Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O, Morgan, Anna, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Ntalla, Ioanna, O'Connell, Jeffrey R, Owen, Katharine R, Pedersen, Oluf, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T, Rasheed, Asif, Raulerson, Chelsea K, Rauramaa, Rainer, Reilly, Dermot F, Reiner, Alex P, Ridker, Paul M, Rivas, Manuel A, Robertson, Neil R, Robino, Antonietta, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J, Small, Kerrin S, Smith, Blair H, Smith, Jennifer A, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E, Strauch, Konstantin, Stringham, Heather M, Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin MA, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, van Duijn, Cornelia M, Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Vuckovic, Dragana, Wagenknecht, Lynne E, Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wareham, Nicholas J, Warren, Helen R, Waterworth, Dawn M, Wessel, Jennifer, White, Harvey D, Willer, Cristen J, Wilson, James G, Wood, Andrew R, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M Carola, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CH, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Rivadeneira, Fernando, Borecki, Ingrid B, Pospisilik, J Andrew, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, Mohlke, Karen L, Rotter, Jerome I, Kutalik, Zoltán, Hirschhorn, Joel N, Cupples, L Adrienne, Loos, Ruth JF, North, Kari E, Lindgren, Cecilia M, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Institute for Molecular Medicine Finland, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, Young, Kristin L [0000-0003-0070-6145], Mahajan, Anubha [0000-0001-5585-3420], Winkler, Thomas W [0000-0003-0292-5421], Locke, Adam E [0000-0001-6227-198X], Medina-Gomez, Carolina [0000-0001-7999-5538], Giri, Ayush [0000-0002-7786-4670], Ng, Maggie CY [0000-0002-4133-2007], Heard-Costa, Nancy L [0000-0001-9730-0306], Manning, Alisa K [0000-0003-0247-902X], Alam, Dewan S [0000-0002-2051-3837], Amouyel, Philippe [0000-0001-9088-234X], Bergmann, Sven [0000-0002-6785-9034], Boehnke, Michael [0000-0002-6442-7754], Butterworth, Adam S [0000-0002-6915-9015], Caulfield, Mark J [0000-0001-9295-3594], Collins, Francis S [0000-0002-1023-7410], de Bakker, Paul IW [0000-0001-7735-7858], Dennis, Joe G [0000-0003-4591-1214], Easton, Douglas F [0000-0003-2444-3247], Elliott, Paul [0000-0002-7511-5684], Evangelou, Evangelos [0000-0002-5488-2999], Giedraitis, Vilmantas [0000-0003-3423-2021], Girotto, Giorgia [0000-0003-4507-6589], Grarup, Niels [0000-0001-5526-1070], Gustafsson, Stefan [0000-0001-5894-0351], Hansen, Torben [0000-0001-8748-3831], Hayward, Caroline [0000-0002-9405-9550], Howson, Joanna MM [0000-0001-7618-0050], Ikram, M Arfan [0000-0003-0372-8585], Jackson, Anne U [0000-0002-9672-2547], Justesen, Johanne M [0000-0002-0484-8522], Kovacs, Peter [0000-0002-0290-5423], Kuulasmaa, Kari [0000-0003-2165-1411], Langenberg, Claudia [0000-0002-5017-7344], Lin, Li-An [0000-0003-2731-1346], Linneberg, Allan [0000-0002-0994-0184], Liu, Ching-Ti [0000-0002-0703-0742], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], MacGregor, Stuart [0000-0001-6731-8142], McCarthy, Mark I [0000-0002-4393-0510], Morgan, Anna [0000-0001-6290-445X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Munroe, Patricia B [0000-0002-4176-2947], Narisu, Narisu [0000-0002-8483-1156], Neville, Matt [0000-0002-6004-5433], Reilly, Dermot F [0000-0002-9456-1364], Rudan, Igor [0000-0001-6993-6884], Saleheen, Danish [0000-0001-6193-020X], Salomaa, Veikko [0000-0001-7563-5324], Sim, Xueling [0000-0002-1233-7642], Small, Kerrin S [0000-0003-4566-0005], Smith, Blair H [0000-0002-5362-9430], Smith, Jennifer A [0000-0002-3575-5468], Southam, Lorraine [0000-0002-7546-9650], Stefansson, Kari [0000-0003-1676-864X], Stirrups, Kathleen E [0000-0002-6823-3252], Stringham, Heather M [0000-0002-2991-6392], Teumer, Alexander [0000-0002-8309-094X], Thompson, Deborah J [0000-0003-1465-5799], Vestergaard, Henrik [0000-0003-3090-269X], Vitart, Veronique [0000-0002-4991-3797], Wang, Carol A [0000-0002-4301-3974], Wessel, Jennifer [0000-0002-7031-0085], Willer, Cristen J [0000-0001-5645-4966], Zeggini, Eleftheria [0000-0003-4238-659X], Rivadeneira, Fernando [0000-0001-9435-9441], Pospisilik, J Andrew [0000-0002-9745-0977], Deloukas, Panos [0000-0001-9251-070X], Mohlke, Karen L [0000-0001-6721-153X], Kutalik, Zoltán [0000-0001-8285-7523], Loos, Ruth JF [0000-0002-8532-5087], Lindgren, Cecilia M [0000-0002-4903-9374], Apollo - University of Cambridge Repository, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Medical and Clinical Psychology, Justice, Anne E., Karaderi, Tugce, Highland, Heather M., Young, Kristin L., Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L., Fine, Rebecca S., Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W., Locke, Adam E., Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie C. Y., Heard-Costa, Nancy L., Feitosa, Mary F., Manning, Alisa K., Willems, Sara M., Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S., Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Broer, Linda, Burt, Amber A., Butterworth, Adam S., Caulfield, Mark J., Cesana, Giancarlo, Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Collins, Francis S., Cook, James P., Cox, Amanda J., Crosslin, David S., Danesh, John, de Bakker, Paul I. W., Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele Di, Dörr, Marcu, Drenos, Fotio, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Fornage, Myriam, Fox, Caroline S., Franks, Paul W., Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Girotto, Giorgia, Gorski, Mathia, Grallert, Harald, Grarup, Niel, Grove, Megan L., Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T., Hayward, Caroline, Heid, Iris M., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jarvik, Gail P., Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M., Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kovacs, Peter, Krämer, Bernhard K., Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Luan, Jian’An, Lyytikäinen, Leo-Pekka, Macgregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas G. D., Mccarthy, Mark I., Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Ntalla, Ioanna, O’Connell, Jeffrey R., Owen, Katharine R., Pedersen, Oluf, Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T., Rasheed, Asif, Raulerson, Chelsea K., Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Ridker, Paul M., Rivas, Manuel A., Robertson, Neil R., Robino, Antonietta, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Blair H., Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin M. A., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, van Duijn, Cornelia M., Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M. Carola, Rivadeneira, Fernando, Borecki, Ingrid B., Pospisilik, J. Andrew, Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, Mohlke, Karen L., Rotter, Jerome I., Kutalik, Zoltán, Hirschhorn, Joel N., Cupples, L. Adrienne, Loos, Ruth J. F., North, Kari E., Lindgren, Cecilia M., APH - Societal Participation & Health, APH - Health Behaviors & Chronic Diseases, APH - Aging & Later Life, Epidemiology and Data Science, and VU University medical center

Subjects
Exome/genetics, Male, ReproGen Consortium, Adipose tissue, Genome-wide association study, Type 2 diabetes, White adipose tissue, Body Mass Index, Animals, Body Fat Distribution, Case-Control Studies, Drosophila, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeostasis, Humans, Lipids, Proteins, Risk Factors, Waist-Hip Ratio, 0302 clinical medicine, Hyperlipidemia, Body fat distribution, 2. Zero hunger, Genetics, 0303 health sciences, INSULIN-RESISTANCE, ADIPOCYTE DIFFERENTIATION, CHD Exome+ Consortium, Genetic Predisposition to Disease/genetics, Drosophila/genetics, RS11209026 POLYMORPHISM, KINASE 7, 1184 Genetics, developmental biology, physiology, T2D-Genes Consortium, 11 Medical And Health Sciences, Body Fat Distribution/methods, RECEPTOR ALK7, ADIPOSE-TISSUE, Gene Frequency/genetics, Genetic Variation/genetics, InterAct, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], genetic association study, RNA splicing, Proteins/genetics, Genome-Wide Association Study/methods, Lipid particle, ExomeBP Consortium, WAIST CIRCUMFERENCE, Waist-Hip Ratio/methods, Biology, EPIC-CVD Consortium, Article, MAGIC Investigators, 03 medical and health sciences, Homeostasis/genetics, Lipids/genetics, All institutes and research themes of the Radboud University Medical Center, medicine, Global Lipids Genetic Consortium, Risk factor, GENOME-WIDE ASSOCIATION, ABDOMINAL ADIPOSITY, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Gene, 030304 developmental biology, 06 Biological Sciences, medicine.disease, Minor allele frequency, GoT2D Genes Consortium, genetics research, TYPE-2 DIABETES SUSCEPTIBILITY, 3111 Biomedicine, Body mass index, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Body fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥ 5%) and 9 low frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology, and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants., Editorial summary: A trans-ethnic exome-wide association study for body fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.

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