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Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

2016; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/srep25853

2045-2322

Qiao Fan, Xiaobo Guo, J. Willem L. Tideman, Katie Williams, Seyhan Yazar, S. Mohsen Hosseini, Laura D. Howe, Beaté St Pourcain, David M. Evans, Nicholas J. Timpson, George McMahon, Pirro G. Hysi, Eva Krapohl, Ya Xing Wang, Jost B. Jonas, Paul N. Baird, Jie Jin Wang, Ching‐Yu Cheng, Yik-Ying Teo, Tien Yin Wong, Xiaohu Ding, Robert Wojciechowski, Terri L. Young, Olavi Pärssinen, Konrad Oexle, Norbert Pfeiffer, Joan E. Bailey‐Wilson, Andrew D. Paterson, Caroline C. W. Klaver, Robert Plomin, Christopher J. Hammond, David A. Mackey, Mingguang He, Seang‐Mei Saw, Cathy Williams, Jeremy A. Guggenheim, Akira Meguro, Alan F. Wright, Alex W. Hewitt, Alvin L. Young, Veluchamy A. Barathi, Andres Metspalu, Andrew D. Paterson, Angela Döring, Anthony P. Khawaja, Barbara E.K. Klein, Beaté St Pourcain, Brian W. Fleck, Caroline C. W. Klaver, Caroline Hayward, Cathy Williams, Cécile Delcourt, Chi Pui Pang, Chiea Chuen Khor, Ching‐Yu Cheng, Christian Gieger, Christopher J. Hammond, Claire L. Simpson, Cornelia M. van Duijn, David A. Mackey, David M. Evans, Dwight Stambolian, Emily Y. Chew, E Shyong Tai, Eva Krapohl, Evelin Mihailov, George Davey Smith, George McMahon, Ginevra Biino, Harry Campbell, Igor Rudan, Ilkka Seppälä, Jaakko Kaprio, James F. Wilson, Jamie E. Craig, J. Willem L. Tideman, Janina S. Ried, Jean‐François Korobelnik, Jeremy A. Guggenheim, Jeremy Fondran, Jie Jin Wang, Jiemin Liao, Wei Zhao, Jing Xie, Joan E. Bailey‐Wilson, John P. Kemp, Jonathan H. Lass, Jost B. Jonas, Jugnoo S. Rahi, Juho Wedenoja, Kari-Matti Mäkelä, Kathryn P. Burdon, Katie Williams, Kay‐Tee Khaw, Kenji Yamashiro, Konrad Oexle, Laura D. Howe, Li Jia Chen, Liang Xu, Lindsay A. Farrer, M. Kamran Ikram, Margaret M. DeAngelis, Margaux A. Morrison, Maria Schäche, Mario Pirastu, Masahiro Miyake, Maurice Yap, Maurizio Fossarello, Mika Kähönen, Milly S. Tedja, Mingguang He, Nagahisa Yoshimura, Nicholas G. Martin, Nicholas J. Timpson, Nicholas J. Wareham, Nobuhisa Mizuki, Norbert Pfeiffer, Olavi Pärssinen, Olli T. Raitakari, Ozren Polašek, Pancy O. S. Tam, Paul J. Foster, Paul Mitchell, Paul N. Baird, Peng Chen, Pirro G. Hysi, Phillippa Cumberland, Puya Gharahkhani, Qiao Fan, René Höhn, Rhys D. Fogarty, Robert Luben, Robert P. Igo, Robert Plomin, Robert Wojciechowski, Ronald Klein, S. Mohsen Hosseini, Sarayut Janmahasatian, Seang‐Mei Saw, Seyhan Yazar, Shea Ping Yip, Sheng Feng, Simona Vaccargiu, Songhomitra Panda‐Jonas, Stuart MacGregor, Sudha K. Iyengar, Taina Rantanen, Terho Lehtimäki, Terri L. Young, Thomas Meitinger, Tien Yin Wong, Tin Aung, Toomas Haller, Véronique Vitart, Vinay Nangia, Virginie J. M. Verhoeven, Vishal Jhanji, Wanting Zhao, Wei Chen, Xiangtian Zhou, Xiaobo Guo, Xiaohu Ding, Ya Xing Wang, Yi Lu, Yik-Ying Teo, Zoran Vatavuk,

Retinal Diseases and Treatments

Abstract Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7–15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E–08) and 2.3% (P = 6.9E–21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4 ; P = 6.3E–04).