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1. Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies

Author

Xuling Chang, Resham L Gurung, Rajkumar Dorajoo, Jianjun Liu, Woon-Puay Koh, Yechiel Friedlander, Kenneth B. Beckman, Chew-Kiat Heng, Wee Yang Meah, Jennifer M. Adams-Haduch, Renwei Wang, Zheng Li, Ling Wang, Sylvia Liu, Su Chi Lim, Chiea Chuen Khor, Yiamunaa M, Jian-Min Yuan, Kar Seng Sim, and Rob M. van Dam

Subjects
0301 basic medicine, Adult, Male, Candidate gene, DNA Repair, Science, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, TINF2, Biology, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, White People, Article, Cohort Studies, 03 medical and health sciences, Young Adult, Telomere Homeostasis, Asian People, Genetics research, Leukocytes, Genetics, SNP, Humans, Prospective Studies, lcsh:Science, Respiratory Tract Infections, Genetic association, Aged, Aged, 80 and over, Singapore, Multidisciplinary, General Chemistry, Middle Aged, Telomere, 021001 nanoscience & nanotechnology, Phenotype, 3. Good health, 030104 developmental biology, Telomeres, lcsh:Q, Female, 0210 nano-technology, Genome-Wide Association Study
Abstract

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P, Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.

Published
2019

2. Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population

Author

Woon-Puay Koh, Yiamunaa M, Chiea Chuen Khor, Ling Wang, Kar Seng Sim, Kenneth B. Beckman, Yechiel Friedlander, Jianjun Liu, Renwei Wang, Jian-Min Yuan, Resham L Gurung, Jennifer M. Adams-Haduch, Jing Xian Teo, Zheng Li, Rob M. van Dam, Sonia Davila, Sylvia Liu, Weng Khong Lim, Xuling Chang, Patrick Tan, Aizhen Jin, Wee Yang Meah, Khung Keong Yeo, Rajkumar Dorajoo, Chew-Kiat Heng, and Su Chi Lim

Subjects
0301 basic medicine, Adult, Male, QH301-705.5, Colorectal cancer, Population, Telomere-Binding Proteins, Medicine (miscellaneous), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Shelterin Complex, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Asian People, Neoplasms, Genetics research, medicine, Leukocytes, SNP, Missense mutation, Humans, Prospective Studies, Biology (General), education, Cancer, Aged, Genetics, Aged, 80 and over, education.field_of_study, Singapore, Telomere Homeostasis, Middle Aged, medicine.disease, Telomere, 030104 developmental biology, Cross-Sectional Studies, 030220 oncology & carcinogenesis, Chronic Disease, Adenocarcinoma, Female, General Agricultural and Biological Sciences
Abstract

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10−14–6.94×10−10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers., Xuling Chang et al. study whether low frequency variants are associated with leukocyte telomere length and whether these variants predispose to incident cancers and mortalities among East Asians. They find that three East Asian specific variants at POT1, TERF1 and STN1 loci are associated with leukocyte telomere length and report a mechanistic pathway linking TERF1, leukocyte telomere length and incident colon cancer.

Published
2021

3. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Daniele Cusi, Etsuo Chihara, Leyla Al-Jasim, Ya Xing Wang, Tero Kivelä, Jinghong Sang, Adeyinka O. Ashaye, Bowen Zhao, Tan Do, Susanne Moebus, Ursula Schlötzer-Schrehardt, Shamira A. Perera, Augustine W O Cheong, Afsaneh Naderi Beni, Francisco A. Escudero-Domínguez, Yoshiaki Kiuchi, Tomomi Higashide, DS Klobassa, Friedrich E. Kruse, Nicole Weisschuh, Chunyan Qiao, Muhammad Imran Khan, Martin L. Hibberd, Arthur J. Sit, Jamie E Craig, Akitoshi Yoshida, Periasamy Sundaresan, Humaira Ayub, Kathryn P. Burdon, Jonathan G Crowston, Kazunori Miyata, Marisa Cruz-Aguilar, Markus M. Nöthen, Hasnaa Lamari, Michael A. Hauser, Louis R. Pasquale, Anneke I. den Hollander, Eija Vesti, Ursula Hoja, Raphael Q Soh, Burcu Kasım, Adeola O Onakoya, Rachel W. Kuchtey, Eugeny L. Akopov, Liang Xu, Juan Carlos Zenteno, Chaiwat Teekhasaenee, Saleh A. Al-Obeidan, Eleftherios Anastasopoulos, Anita S Y Chan, Nagahisa Yoshimura, John Kuchtey, Naris Kitnarong, Yaan Fun Chong, Boonsong Wanichwecharugruang, R.R. Fayzrakhmanov, Paul Mitchell, N Kalpana, Unnur Thorsteinsdottir, Kei Tashiro, Rajesh Kumar, Jin Wook Jeoung, Deepak P. Edward, Frederico Martinon-Torres, Bilge Batu, Anavaj Sakuntabhai, Robert N. Weinreb, Héctor González-Iglesias, Sasan Moghimi, Jia Nee Foo, Nkechi J Uche, Karen Curtin, Kenji Inoue, Lingam Vijaya, Makoto Aihara, Dilek Aktas, Norimoto Gotoh, Wasu Supakontanasan, Laura Dallorto, Takako Sugimoto, Jonathan L. Haines, Olusola Olawoye, Janey L. Wiggs, Sripriya Sarangapani, Craig J. Chaya, Theofanis Pappas, Fotis Topouzis, Eranga N. Vithana, Steffen Heegaard, Fridbert Jonasson, Kazuhiko Mori, Idakwo Ugbede, Hongyan Jia, Anthi Chatzikyriakidou, Robert P. Igo, Soon Cheol Cha, Yueming Chen, Su-Ling Ho, Zhenglin Yang, Jost B. Jonas, Francesca Pasutto, Ken Hayashi, Rahat Husain, Georg Mossböck, S Fabian Lerner, R. Rand Allingham, Priti Sahay, Fumihiko Matsuda, Yanin Suwan, Teresa Rolle, Robert Ritch, Peter Kraft, Trevor R. Carmichael, Kar Seng Sim, Raheel Qamar, Gordana Sunaric Megevand, Tomasz Zarnowski, Shazia Micheal, Scott Thomas, Paolo Frezzotti, Vera Vysochinskaya, Linda M. Zangwill, Alina Popa Cherecheanu, Tin Aung, Jessica N. Cooke Bailey, Kyu Hyung Park, Edward Dervan, Suhanya Okeke, Pablo Fornero, Sidi M Ezzouhairi, Pascal Reynier, Gudmar Thorleifsson, Michael V. Dubina, Kazuhisa Sugiyama, Sylvain Roy, Per Kappelgaard, Mineo Ozaki, Vijayan Saravanan, Carlo Lavia, Wenda L. Greer, Takanori Mizoguchi, Alireza Lashay, A. Binder, Daniel Berner, Su Qin Peh, Balram Chowbay, Nino Kobakhidze, Ifeoma N. Asimadu, Delia Sivori, Gopalakrishnan Prakadeeswari, Alexandros Lambropoulos, Michael Coote, Sergei Y. Astakhov, Shahin Yazdani, Dan Milea, Montserrat García, Lydia Álvarez, Kenji Yamashiro, Soumya Raychaudhuri, Pratap Challa, Aparna Rao, Jae H. Kang, Khai Koon Heng, Richard K. Lee, Tien Yin Wong, Alex W. Hewitt, Yoko Ikeda, Kessara Pathanapitoon, Panayiota Founti, Daniella Bach-Holm, Emmanuelle Souzeau, Margaret A. Pericak-Vance, Michèle Ramsay, Nkiru Kizor-Akaraiwe, Yosai Mori, Antonio Maria Fea, Chandrashekaran Shivkumar, Xiao Yu Ng, Jie Jin Wang, Erika Salvi, Giang T T Nguyn, Steffen Uebe, Tamara Zompa, Anne L. Coleman, Werner Zenz, Min Sagong, Luis Fernández-Vega Cueto, Farah Akhtar, Susan Williams, Sarah C. Nelson, Bradford J. Shingleton, Ryuichi Ideta, Leon W. Herndon, Zheng Li, Murat Irkec, M. Roy Wilson, Ewa Kosior-Jarecka, Christian Y. Mardin, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Abderrahman Rafei, Rengaraj Venkatesh, Stefan Herms, George Chichua, Mohammad Pakravan, Robyn M. Rautenbach, Shi Qi Mok, Trình V Nguyn, Patricio G. Schlottmann, Nassim Khatibi, Daniel Gaston, Masaru Inatani, Morio Ueno, Mukharram M. Bikbov, Eoin Silke, Homa Naderifar, Linda Hansapinyo, Paolo Manunta, Z. Xie, Urszula Lukasik, Eray Atalay, Lulin Huang, Xuyang Liu, Chie Sotozono, Shuang Ru Goh, John H. Fingert, Richard A. Mills, Khaled K. Abu-Amero, Xiao Yin Chen, Matthias Zenkel, Sergo Tabagari, Irma Järvelä, Xueyi Chen, Stéphanie Leruez, Yury S. Astakhov, Sonia Davila, Yildirim Nilgün, Ronnie George, Shin-ichi Manabe, Miguel Coca-Prados, Masahiro Miyake, Ignacio Lischinsky, Rogelio González-Sarmiento, Arkasubhra Ghosh, A. Emelyanov, Çilingir Oguz, Masakazu Nakano, Rohit Shetty, Karen Bedard, Toshiya Sakurai, Yutao Liu, Barbara M Wirostko, Hui Zhang, Ulrich-Christoph Welge-Luessen, Toshiaki Kubota, Vania Castro, Hip X Nguyn, Liyun Jia, Ari Ziskind, Hideki Chuman, Andrew C. Orr, Satoko Nakano, Daniela Paoli, Masahide Yanagi, Aravind Haripriya, Kari Stefansson, Pedro Pablo Rodríguez-Calvo, Hui Meng Soo, Chiea Chuen Khor, Gyulli M. Kazakbaeva, Osvaldo Cuello, Mei Chin Lee, Ki Ho Park, Natalia Porporato, Lourdes de Juan Marcos, Ching-Yu Cheng, Shigeyasu Kazama, Shigeru Kinoshita, Axel M. Hillmer, Alan S. Crandall, Victor H. K. Yong, Ohoud Owaidhah, Rodolfo Perez Grossmann, Jeeyun Ahn, André Reis, Nevbahar Tamçelik, Satoshi Ishiko, Antonio Salas, Ningli Wang, Singapore Eye Research Institute [Singapore] (SERI), Ozaki Eye Hospital [Miyazaki], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), deCODE genetics [Reykjavik], Mizoguchi Eye Hospital [Sasebo], Case Western Reserve University [Cleveland], Aravind Eye Hospital [Madurai, India], University of the Witwatersrand [Johannesburg] (WITS), Pavlov First Saint Petersburg State Medical University [St. Petersburg], Dalhousie University [Halifax], Flinders University [Adelaide, Australia], Kyoto Prefectural University of Medicine [Kyoto, Japon], King Saud University [Riyadh] (KSU), Genome Institute of Singapore (GIS), Aravind Medical Research Foundation (AMRF), Université de Médecine Carol Davila, Harvard Medical School [Boston] (HMS), University of Washington [Seattle], Hayashi Eye Hospital [Fukuoka], Shinjo Eye Clinic [Nagoya], Medical University of Lublin, Inoue Eye Hospital [Tokyo], Hacettepe University = Hacettepe Üniversitesi, Universidad de Oviedo [Oviedo], Kanazawa University (KU), Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Organizacion Medica de Investigacion (OMI BUENOS AIRES), Fundacion para el Estudio del Glaucoma [Buenos Aires], Chercheur indépendant, Eskisehir Osmangazi University, Ufa Eye Research Institute [Bashkortostan], Seoul National University Hospital, Yeungnam University [South Korea], Kyoto University, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Universität Heidelberg [Heidelberg] = Heidelberg University, Birla Institute of Scientific Research (BISR), B. M. Birla Science and Technology Center, Faculty of Computer Science, Department of Pathology and Immunology, Geneva University Hospital (HUG), Key Laboratory for Information System Security, ministry of education, Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media (NACHOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Department of Ophthalmology, School of Medicine [Thessaloniki, Grèce], Aristotle University of Thessaloniki, Università degli Studi di Siena = University of Siena (UNISI), Department of Medicine, Surgery, and Dentistry, University of Milano, Japan Advanced Institute of Science and Technology (JAIST), Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Archaeogenetics Laboratory, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Rheinische Friedrich-Wilhelms-Universität Bonn, University of Kentucky (UK), Helsinki University Eye Hospital, Turku University Hospital, Turku, Finland, COMSATS Institute of Information Technology (CIIT), Department of Epidemiology, Harvard School of Public Health, University of Miami Leonard M. Miller School of Medicine (UMMSM), Brigham and Women's Hospital [Boston], Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen, University of Copenhagen = Københavns Universitet (UCPH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of California [San Diego] (UC San Diego), University of California (UC), University of Iceland [Reykjavik], New York Eye and Ear Infirmary of Mount Sinai [New York] (NYEE), Oita University Faculty of Medicine [Oita, Japon], Radboud University Medical Center [Nijmegen], Oogheelkunde, RS: FHML non-thematic output, Kyoto University [Kyoto], Universidad Nacional Autónoma de México (UNAM), Universität Heidelberg [Heidelberg], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (JAD), Dipartimento di Scienze oftalmologiche e Neurochirurgiche, Universita' degli Studi di Siena, Siena, Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rothschild Hospital, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Kentucky, University of Copenhagen = Københavns Universitet (KU), University of California, Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlötzer Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P, Haripriya, Aravind, Williams, Susan E, Astakhov, Yury S, Orr, Andrew C, Burdon, Kathryn P, Nakano, Satoko, Mori, Kazuhiko, Abu Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H, Nelson, Sarah, Hayashi, Ken, Manabe, Shin Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C, Jonas, Jost B, Kumar, Rajesh S, Perera, Shamira A, Chan, Anita S. Y, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P, de Juan Marcos, Lourde, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthia, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge Luessen, Ulrich Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofani, Anastasopoulos, Eleftherio, Lambropoulos, Alexandro, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R, Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz Aguilar, Marisa, Ezzouhairi, Sidi M, Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K, Khan, Muhammad Imran, Olawoye, Olusola O, Ashaye, Adeyinka O, Ugbede, Idakwo, Onakoya, Adeola, Kizor Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J, Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Grossmann, Rodolfo Perez, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A, Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W, Coote, Michael, Crowston, Jonathan G, Astakhov, Sergei Y, Akopov, Eugeny L, Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al Obeidan, Saleh A, Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q, Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O, Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su Ling, Hillmer, Axel M, Cheng, Ching Yu, Escudero Domínguez, Francisco A, González Sarmiento, Rogelio, Martinon Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Nari, Sakuntabhai, Anavaj, Nguyn, Hip X, Nguyn, Giang T. T, Nguyn, Trình V, Zenz, Werner, Binder, Alexander, Klobassa, Daniela S, Hibberd, Martin L, Davila, Sonia, Herms, Stefan, Nöthen, Markus M, Moebus, Susanne, Rautenbach, Robyn M, Ziskind, Ari, Carmichael, Trevor R, Ramsay, Michele, Álvarez, Lydia, García, Montserrat, González Iglesias, Héctor, Rodríguez Calvo, Pedro P, Cueto, Luis Fernández Vega, Oguz, Çilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasım, Burcu, Wilson, M. Roy, Coleman, Anne L, Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W, Kuchtey, John, Curtin, Karen, Chaya, Craig J, Crandall, Alan, Zangwill, Linda M, Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I, Vesti, Eija, Fingert, John H, Lee, Richard K, Sit, Arthur J, Shingleton, Bradford J, Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak Vance, Margaret A, Raychaudhuri, Soumya, Heegaard, Steffen, Kivelä, Tero, Reis, André, Kruse, Friedrich E, Weinreb, Robert N, Pasquale, Louis R, Haines, Jonathan L, Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N, Micheal, Shazia, Topouzis, Foti, Craig, Jamie E, Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L, Pasutto, Francesca, Khor, Chiea Chuen, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and University of Helsinki

Subjects
0301 basic medicine, Male, Calcium Channels/genetics, Messenger, Medizin, PSEUDOEXFOLIATION SYNDROME, Genome-wide association study, BLOOD-PRESSURE, Disease, Exfoliation Syndrome, Eye, Exfoliation Syndrome/ethnology/genetics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, PARKINSONS-DISEASE, 80 and over, ta319, Missense mutation, Genetics, Aged, 80 and over, Amino Acid Oxidoreductases/genetics/physiology, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian Continental Ancestry Group, Calcium Channels, Cell Adhesion, Extracellular Matrix, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Haplotypes, Humans, Molecular Chaperones, RNA, Messenger, Spheroids, Cellular, Genome-Wide Association Study, Mutation, Missense, Point Mutation, Metaanalysis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, ALZHEIMERS-DISEASE, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Molecular Chaperones/biosynthesis/genetics, Biology, SYNONYMOUS MUTATIONS, ta3111, Article, 03 medical and health sciences, Asian People, Asian Continental Ancestry Group/genetics, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, Risk factor, GENOME-WIDE ASSOCIATION, Eye/metabolism, Aged, Genetic association, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Individuals, Glaucoma, Odds ratio, Extracellular Matrix/metabolism, RNA, Messenger/biosynthesis, MACULAR DEGENERATION, RISK LOCI, eye diseases, COMMON SEQUENCE VARIANTS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, 030221 ophthalmology & optometry, RNA, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cellular, Spheroids, Missense, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Polymorphisms, purl.org/pe-repo/ocde/ford#1.06.07 [https], INFLAMMATORY-BOWEL-DISEASE
Abstract

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017
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4. Variation at HLA-DRB1 is associated with resistance to enteric fever

Author

Jeremy Farrar, Tin Aung, Amit Arjyal, Nguyen Phu Huong Lan, Kar Seng Sim, Le Thi Phuong, Trinh T. B. Tram, Phat Voong Vinh, Cameron P. Simmons, Soumya Raychaudhuri, Stephen Baker, Tran Tinh Hien, Nguyen Tran Chinh, Jia Nee Foo, Nga Tran Vu Thieu, Buddha Basnyat, Zheng Li, Nguyen Thi Hue, Abhilasha Karkey, Yukinori Okada, Katherine L. Anders, Do Nu Hon, Sarah J. Dunstan, Martin L. Hibberd, Olita Shilpakar, Christopher M. Parry, Yik Ying Teo, Ha Vinh, Paul I.W. de Bakker, Chiea Chuen Khor, Buhm Han, Mai Ngoc Lanh, Tan Do, Christiane Dolecek, Sabina Dongol, and Samir Koirala

Subjects
Genetic Markers, Genotype, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Typhoid fever, Article, Nepal, Genetics, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, Allele, Typhoid Fever, HLA-DRB1, Alleles, Antigen Presentation, Principal Component Analysis, Models, Statistical, Chromosome Mapping, Odds ratio, medicine.disease, Virology, Minor allele frequency, Vietnam, Genetic marker, Immunology, biology.protein, Regression Analysis, Biomarkers, HLA-DRB1 Chains
Abstract

Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C1. We conducted a genome-wide association study of 432 individuals with blood culture–confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10−10), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10−11) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.

Published
2016
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5. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study

Author

Miriam Tao, Suk Teng Chin, Li Na Feng, Richard Quek, Choon Kiat Ong, Yukinori Okada, Yi Xin Zeng, Qing Qing Cai, Yan Hui Liu, Lay Poh Khoo, Wen Sheng Liu, Yurike Laurensia, Wee Yang Meah, Fen Zhang, Maarja-Liisa Nairismagi, Jing Cui, Soo Yong Tan, Wee Joo Chng, Richard P. Ebstein, Jeslin Chian Hung Ha, Farid Mohamad, Kar Seng Sim, Soumya Raychaudhuri, Rou Jun Peng, Yi Xia, Jia Nee Foo, Chi Pui Pang, Colin Phipps Diong, Qi Sheng Feng, Li Zhen Chen, Jianjun Liu, Tiffany Tang, Siok Bian Ng, Soon Thye Lim, Chiea Chuen Khor, Soo Hong Chew, Jin Xin Bei, Wen Tan, Tin Aung, Balram Chowbay, Hong Min Li, Yun Miao Guo, Bin Tean Teh, Jie Rong Chen, Zheng Li, and Li Jia Chen

Subjects
0301 basic medicine, Adult, Male, Linkage disequilibrium, China, Herpesvirus 4, Human, Lymphoma, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, Risk Factors, Biomarkers, Tumor, Medicine, Humans, Genetic Predisposition to Disease, Young adult, Aged, Neoplasm Staging, business.industry, Haplotype, Case-control study, Odds ratio, Middle Aged, Prognosis, Lymphoma, Extranodal NK-T-Cell, Killer Cells, Natural, 030104 developmental biology, Oncology, Case-Control Studies, Natural Killer T-Cells, Female, business, Imputation (genetics), Demography, Follow-Up Studies, Genome-Wide Association Study
Abstract

Summary Background Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. Methods We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. Findings Associations exceeding the genome-wide significance threshold (p −8 ) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1 ) having the strongest association with NKTCL susceptibility (p=4·21 × 10 −19 , odds ratio [OR] 1·84 [95% CI 1·61–2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10 −14 ). This association is distinct from MHC associations with Epstein-Barr virus infection. Interpretation To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. Funding Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).

Published
2016

6. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Author

Liang Xu, Jessica N. Cooke Bailey, Seyhan Yazar, Janey L. Wiggs, Jost B. Jonas, Victor Koh, Adriana I Iglesias, Yik Ying Teo, Henriët Springelkamp, Tim D. Spector, Puya Gharahkhani, Tin Aung, Nomdo M. Jansonius, Chiea Chuen Khor, Jonathan L. Haines, André G. Uitterlinden, Xiaoyan Luo, René Höhn, Arne Schillert, Paul G. Sanfilippo, Abhishek Nag, Christopher J Hammond, Louis R. Pasquale, Albert Hofman, Hannah Forward, Pirro G. Hysi, Hans G Lemij, Lisa S. Kearns, Ben A. Oostra, Elisabeth M. van Leeuwen, Ayse Demirkan, Caroline C W Klaver, Paulus T. V. M. de Jong, Ching-Yu Cheng, Najaf Amin, E-Shyong Tai, Roger C. W. Wolfs, Alex W. Hewitt, Stuart MacGregor, Cornelia M. van Duijn, Tiger Zhou, Wishal D. Ramdas, Fernando Rivadeneira, Jamie E Craig, Kathryn P. Burdon, David A. Mackey, Seng-Chee Loon, Norbert Pfeiffer, Johannes R. Vingerling, Sven J. van der Lee, Aniket Mishra, Kar Seng Sim, Terri L. Young, Tien Yin Wong, Seang-Mei Saw, Eranga N. Vithana, Karl J. Lackner, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, MUMC+: MA UECM Oogartsen ZL (9), MUMC+: MA UECM Oogartsen MUMC (9), RS: FHML non-thematic output, Netherlands Institute for Neuroscience (NIN), and Perceptual and Cognitive Neuroscience (PCN)

Subjects
Aging, genetic structures, Epidemiology, Optic disk, Glaucoma, Genome-wide association study, Neurodegenerative, Eye, Optic neuropathy, Optic Nerve Diseases, NERVE, GWAS, Genetics (clinical), Genetics, NEIGHBORHOOD Consortium, ATOH7, Asians, medicine.anatomical_structure, cup area, Optic nerve, Public Health and Health Services, OPEN-ANGLE GLAUCOMA, TRAITS, Optic disc, Asian Continental Ancestry Group, medicine.medical_specialty, Open angle glaucoma, European Continental Ancestry Group, Optic Disk, Quantitative Trait Loci, Biology, OCULAR-TISSUES, Retinal ganglion, Article, White People, Asian People, Ophthalmology, medicine, Humans, disc area, Eye Disease and Disorders of Vision, Whites, Human Genome, Neurosciences, GENOTYPES, medicine.disease, GENE, eye diseases, SIZE, glaucoma, sense organs, Genome-Wide Association Study
Abstract

Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma. ? 2015

Published
2015

7. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility

Author

Rashmi Gupta, Colin Theng, Jianjun Liu, Mona Ståhle, Jia Nee Foo, Yi Li, Wolfgang Lieb, Caihong Zhu, Wilson Liao, Kar Seng Sim, Fabio Sánchez, Ling Wang, Gerald G. Krueger, Xianbo Zuo, Herty Liany, Joseph J. Catanese, Xuejun Zhang, Yik-Ying Teo, Mark Seielstad, Philip L. De Jager, Hui Qi Low, Yonghong Li, Liangdan Sun, Leonid Padyukov, Kristina Callis Duffin, Abrar A. Qureshi, Eva Ellinghaus, Andre Franke, Michael Weichenthal, Changbing Shen, Sören Mucha, Xavier Estivill, Paul I.W. de Bakker, Anne M. Bowcock, Ishak D. Irwan, Jiali Han, Stephan Weidinger, Anping Zhang, and Xianyong Yin

Subjects
Interferon-Induced Helicase, IFIH1, Ethnic group, Genes, MHC Class I, General Physics and Astronomy, Genome-wide association study, Disease, DISEASE, DEAD-box RNA Helicases, Genetics, Multidisciplinary, Interleukin-12 Subunit p40, COMMON VARIANTS, 3. Good health, Multidisciplinary Sciences, HLA, DIFFERENTIATION, Core Binding Factor Alpha 2 Subunit, Science & Technology - Other Topics, Allelic heterogeneity, Asian Continental Ancestry Group, RUNX1, HAPLOTYPE MAP, European Continental Ancestry Group, Human leukocyte antigen, Biology, Article, White People, General Biochemistry, Genetics and Molecular Biology, Asian People, Psoriasis, MD Multidisciplinary, medicine, Humans, Genetic Predisposition to Disease, CHINESE POPULATION, Psoriasi, Science & Technology, Tumor Suppressor Proteins, Case-control study, General Chemistry, medicine.disease, RISK LOCI, Genetic architecture, Adaptor Proteins, Vesicular Transport, LUNG ADENOCARCINOMA, Case-Control Studies, EXPLAIN, Genome-Wide Association Study, Transcription Factors
Abstract

Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations., Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here Yin et al. conduct a large trans-ethnic genome-wide meta-analysis and identify novel loci that contribute to population-specific susceptibility.

Published
2015

8. Natural positive selection and north–south genetic diversity in East Asia

Author

Jieming Chen, Jianjun Liu, E-Shyong Tai, Kar Seng Sim, Kee Seng Chia, Xuejun Zhang, Chen Suo, Wan Ting Tay, Tien Yin Wong, Chiea Chuen Khor, Xueling Sim, Yik Ying Teo, Haiyan Xu, Rick Th Ong, and Yi Xin Zeng

Subjects
Linkage disequilibrium, Population genetics, Genes, MHC Class I, Single-nucleotide polymorphism, HapMap Project, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Gene Frequency, Genetic variation, Genetics, Ethnicity, Humans, International HapMap Project, Selection, Genetic, Genetics (clinical), Genetic association, Genetic diversity, Asia, Eastern, Genome, Human, Altitude, Homozygote, Computational Biology, Genetic Variation, Genetics, Population, Haplotypes, Evolutionary biology, Imputation (genetics)
Abstract

Recent reports have identified a north–south cline in genetic variation in East and South-East Asia, but these studies have not formally explored the basis of these clinical differences. Understanding the origins of these variations may provide valuable insights in tracking down the functional variants in genomic regions identified by genetic association studies. Here we investigate the genetic basis of these differences with genome-wide data from the HapMap, the Human Genome Diversity Project and the Singapore Genome Variation Project. We implemented four bioinformatic measures to discover genomic regions that are considerably differentiated either between two Han Chinese populations in the north and south of China, or across 22 populations in East and South-East Asia. These measures prioritized genomic stretches with: (i) regional differences in the allelic spectrum for SNPs common to the two Han Chinese populations; (ii) differential evidence of positive selection between the two populations as quantified by integrated haplotype score (iHS) and cross-population extended haplotype homozygosity (XP-EHH); (iii) significant correlation between allele frequencies and geographical latitudes of the 22 populations. We also explored the extent of linkage disequilibrium variations in these regions, which is important in combining genetic association studies from North and South Chinese. Two of the regions that emerged are found in HLA class I and II, suggesting that the HLA imputation panel from the HapMap may not be directly applicable to every Chinese sample. This has important implications to autoimmune studies that plan to impute the classical HLA alleles to fine map the SNP association signals.

Published
2011

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