209 Candidate Genes in Myopia Susceptibility
has yet to be assessed in the Singaporean SCORM cohort, the evidence for association observed in the Caucasian cohorts thus far are convincing.
Concluding Remarks
In conclusion, some clear patterns are emerging in the field of refractive error genetics. Altered susceptibility to myopia in humans appears to be highly polygenic with many genetic loci initially implicated, but only a minority of these have been convincingly replicated in subsequent studies. Most identified loci have relatively small effects with low odds ratios (< 3), the exceptions being monogenic disorders, which also result in severe myopia (e.g. Stickler’s syndrome). Genome-wide linkage analysis of family members (e.g. twins) has recently shown some success in defining broad susceptibility loci for myopia. Despite this, many follow-up studies leading from genome-wide linkage analysis fail to identify the causative genetic variants underlying the broad linkage peaks.
Heterogeneity of genotypic and allelic association findings are frequently observed when comparing results between different study cohorts. The most obvious cause for this is the non-uniform phenotype definition across study populations (e.g. definitions of myopia vary from between SE ≤ –0.5 D to SE ≤ –0.75 D across studies, with some considering SE ≤ –1.0 D; for severe myopia, definitions have varied from SE ≤ –5.0 D to SE ≤ –10.0 D). Other possible reasons include different susceptibility genes for different ethnic groups, as well as undetected epistasis within certain population groups, which may mask true associations. As the contribution of environmental factors to myopia pathogenesis is considerable, future efforts should involve more precise inclusion of environmental covariates within multi-variate modelling frameworks in the attempt to accurately control for them in genetic studies. Finally, the possibility of a considerable number of these results being false positives should not be dismissed.
These provisional conclusions are currently being altered by the great promise of genome-wide association studies that could revolutionize our approach to the genetic analysis of myopia. Indeed, platforms that simultaneously genotype a million SNPs in each participating individual are now widely available. The recent availability of genome-wide interrogation of structural variants (e.g. copy number variants) and second generation ‘deep sequencing’ facilities will enable researchers to take into account the ‘total
210 C.-C. Khor
individual genetic variation’ beyond single-marker analysis. This will allow for much improved genotype-phenotype correlation using advanced analysis frameworks, and advance our understanding in the pathogenesis mechanisms of myopia development and progression.
Acknowledgments
The Agency for Science, Technology and Research (A-STAR), and the National University of Singapore — Genome Institute of Singapore (NUS — GIS) Center for Molecular Epidemiology (CME) provided funding for the SCORM studies. The author is an A-STAR scholar and currently holds an adjunct appointment at the NUS-GIS CME.
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