A genetic epidemiological study of myopia : identification of myopia susceptibility genes

Abstract

Myopia is a complex disease. People with high degrees of myopia have a greater chance of developing irreversible visual impairment. Myopia becomes epidemic in East Asia with no exception in Hong Kong. The financial burden is increased for the health care system in these regions. The development of high myopia must be controlled in order to solve the problem. The aim of this project was to identify susceptibility genes for high myopia by case-control association studies in a Chinese population. Eleven genes with possible ocular functions and/or within the chromosomal locations of MYP loci were selected. Common representative single nucleotide polymorphisms (SNPs) of the candidate genes were genotyped for a discovery sample set and, if significant association was demonstrated, a replication sample set. Three genes VIPR2, ARHGEF12 and SEPT4 were identified as novel susceptibility genes for high myopia. Association signals were revealed for the ZNF275, but the association signals were in opposite directions. Seven other genes (EGR1, JUN, FOS, VIP, APOE, COX11 and DHX40) were unlikely to be important in the genetic susceptibility to high myopia because significant association was not demonstrated. A pilot genome-wide association study (GWAS) (100 cases and 100 controls) was conducted. Follow-up study was conducted using the above-mentioned two sample sets for 20 top-ranking SNPs that are predicted to have functional effects or are located within MYP loci. Significant association was established for a SNP (rs11079899) and its haplotypes located on chromosome 17, a region flanked by two genes COL1A1 and SUMO2P7. This is the first GWAS to report the involvement of chromosome 17 in high myopia. An in-depth study of the HGF gene, a reported myopia susceptibility gene, was also undertaken to systematically refine the causal region. Three main findings were discovered. First, the involvement of HGF in high myopia was replicated. Second, the causal region was refined. In addition, our results were also consistent with published data. In conclusion, the hypothesis-driven approach successfully identified three novel myopia susceptibility genes while the hypothesis-free approach established an associated region on chromosome 17. In-depth study of HGF enabled the causal region to be refined.