Introduction

164 L.K. Goh, R. Metlapally and T. Young

Human molecular genetic studies to understand the pathogenesis of non-syndromic myopia have been carried out over the last two decades. These include mapping studies with relatively small number of families affected by pathologic myopia and large family-based/case-control genetic association studies based on positional candidate gene approach. The first study to define a genetic interval for myopia on chromosome Xq28 (MYP1, OMIM 310460) was regarding an X-linked recessive form of high myopia named the Bornholm (Denmark) Eye Disease (BED), the phenotype that also included cone dysfunction.21 Since then, numerous loci have been identified for non-syndromic myopia, a detailed list of which is shown in Table 1. The loci on chromosomal regions Xq28, 2q37, 12q21, 18p11, and 22q12 have been replicated independently22–28 as several new ones are being discovered. The involvement of multiple loci suggests that myopia development perhaps is driven by polygenic influences. This notion was corroborated by Klein et al. in their investigation of familial aggregation and pattern of inheritance of ocular refraction in a large cohort (data from the Beaver Dam Eye Study).16

Single nucleotide polymorphism association studies or genome-wide association studies (GWAS) in myopia genetics research have burgeoned in recent years. The approach has been widely used for the discovery of genetic variants associated with common diseases such as bipolar disorder, type 2 diabetes, Crohn’s disease, and cancer.29–32 This has been made possible by the completion of the Human Genome and HapMap projects as well as development of high-throughput genotyping technology for interrogating thousands of single nucleotide polymorphisms (SNPs). In these studies, SNPs across the genome are genotyped and each marker is analyzed individually for association with the trait. It is based on the rationale that some of these markers that are observable (or genotyped) are in linkage disequilibrium with the quantitative trait locus (QTL) which is often not observable or typed. This simple approach of ‘association by guilt’ has led to the discovery of novel disease susceptible genes.

To date, approximately 15 genes have been positively associated with myopia disease status — a list of these is shown in Table 2. In these studies, establishing replication in independent and/or diverse datasets is critical for success in identifying the causative gene/s. While there are studies that have reported lack of association between myopia and some of the listed genes in Table 2,33–40 the reasons for the lack of association can be multifold (sample size, study design, heterogeneity, etc). Since inconsistent and incompatible results can act as a hindrance to gene discovery, we

167 New Approaches in the Genetics of Myopia

Table 2. List of Genetic Association Studies of Genes with Positive Association with Myopic Refractive Error States. PMID — PubMed Unique Identifier. D-diopter