Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium
Authors: Fan Qiao , Guo Xiaobo , Tideman J. Willem L. , Williams Katie M. , Yazar Seyhan , Hosseini S. Mohsen , Howe Laura D. , Pourcain Beaté St , Evans David M. , Timpson Nicholas J. , McMahon George , Hysi Pirro G. , Krapohl Eva , Wang Ya Xing , Jonas Jost B. , Baird Paul Nigel , Wang Jie Jin , Cheng Ching-Yu , Teo Yik-Ying , Wong Tien-Yin , Ding Xiaohu , Wojciechowski Robert , Young Terri L. , Pärssinen Olavi , Oexle Konrad , Pfeiffer Norbert , Bailey-Wilson Joan E. , Paterson Andrew D. , Klaver Caroline C. W. , Plomin Robert , Hammond Christopher J. , Mackey David A. , He Mingguang , Saw Seang-Mei , Williams Cathy , Guggenheim Jeremy A. ,   The CREAM Consortium, Meguro Akira , Wright Alan F. , Hewitt Alex W. , Young Alvin L. , Veluchamy Amutha Barathi , Metspalu Andres , Paterson Andrew D. , Döring Angela , Khawaja Anthony P. , Klein Barbara E. , Pourcain Beate St , Fleck Brian , Klaver Caroline C. W. , Hayward Caroline , Williams Cathy , Delcourt Cécile , Pang Chi Pui , Khor Chiea-Chuen , Cheng Ching-Yu , Gieger Christian , Hammond Christopher J. , Simpson Claire L. , van Duijn Cornelia M. , Mackey David A. , Evans David M. , Stambolian Dwight , Chew Emily , Tai E-Shyong , Krapohl Eva , Mihailov Evelin , Smith George Davey , McMahon George , Biino Ginevra , Campbell Harry , Rudan Igor , Seppälä Ilkka , Kaprio Jaakko , Wilson James F. , Craig Jamie E. , Tideman J. Willem L. , Ried Janina S. , Korobelnik Jean-François , Guggenheim Jeremy A. , Fondran Jeremy R. , Wang Jie Jin , Liao Jiemin , Zhao Jing Hua , Xie Jing , Bailey-Wilson Joan E. , Kemp John P. , Lass Jonathan H. , Jonas Jost B. , Rahi Jugnoo S. , Wedenoja Juho , Mäkelä Kari-Matti , Burdon Kathryn P. , Williams Katie M , Khaw Kay-Tee , Yamashiro Kenji , Oexle Konrad , Howe Laura D. , Chen Li Jia , Xu Liang , Farrer Lindsay , Ikram M. Kamran , Deangelis Margaret M. , Morrison Margaux , Schache Maria , Pirastu Mario , Miyake Masahiro , Yap Maurice K. H. , Fossarello Maurizio , Kähönen Mika , Tedja Milly S. , He Mingguang , Yoshimura Nagahisa , Martin Nicholas G. , Timpson Nicholas J. , Wareham Nick J. , Mizuki Nobuhisa , Pfeiffer Norbert , Pärssinen Olavi , Raitakari Olli , Polasek Ozren , Tam Pancy O. , Foster Paul J. , Mitchell Paul , Baird Paul Nigel , Chen Peng , Hysi Pirro G. , Cumberland Phillippa , Gharahkhani Puya , Fan Qiao , Höhn René , Fogarty Rhys D. , Luben Robert N. , Igo Jr Robert P. , Plomin Robert , Wojciechowski Robert , Klein Ronald , Mohsen Hosseini S. , Janmahasatian Sarayut , Saw Seang-Mei , Yazar Seyhan , Ping Yip Shea , Feng Sheng , Vaccargiu Simona , Panda-Jonas Songhomitra , MacGregor Stuart , Iyengar Sudha K. , Rantanen Taina , Lehtimäki Terho , Young Terri L. , Meitinger Thomas , Wong Tien-Yin , Aung Tin , Haller Toomas , Vitart Veronique , Nangia Vinay , Verhoeven Virginie J. M. , Jhanji Vishal , Zhao Wanting , Chen Wei , Zhou Xiangtian , Guo Xiaobo , Ding Xiaohu , Wang Ya Xing , Lu Yi , Teo Yik-Ying , Vatavuk Zoran 
Published: May 2016

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).