Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.
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).
Fan, Q; Guo, X; Tideman, JWL; Williams, KM; Yazar, S; Hosseini, SM; Howe, LD; Pourcain, BS; Evans, DM; Timpson, NJ; McMahon, G; Hysi, PG; Krapohl, E; Wang, YX; Jonas, JB; Baird, PN; Wang, JJ; Cheng, C-Y; Teo, Y-Y; Wong, T-Y; Ding, X; Wojciechowski, R; Young, TL; Pärssinen, O; Oexle, K; Pfeiffer, N; Bailey-Wilson, JE; Paterson, AD; Klaver, CCW; Plomin, R; Hammond, CJ; Mackey, DA; He, M; Saw, S-M; Williams, C; Guggenheim, JA; CREAM Consortium,
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