A genetic epidemiologic study of candidate genes involved in the optic nerve head morphology

The size of the optic nerve head, referred to as disc area (DA), and the vertical cup-disc ratio (VCDR), are clinically relevant parameters for glaucomatous optic neuropathy. Although these measures have a high heritability, little is known about the underlying genes. Previously, the genes SALL1 and SIX1 were found to be genome-wide significantly associated with DA and VCDR. The purpose of the present study was to investigate whether genes encoding protein known to interact with protein encoded by SALL1 and SIX1 are also associated with either DA or VCDR.

A total of 38 candidate genes were chosen covering all known proteins interacting with SALL1 and SIX1. These were initially studied in the Rotterdam Study (RS)-I, including 5312 Caucasian subjects characterized for DA and VCDR. Positive findings were further investigated in two independent cohorts (RS-II and RS-III) and finally replicated in a fourth population (ERF). Bonferroni correction was applied to the meta-analyses.

Three loci were found to be associated with DA. The only locus significant after correcting for multiple testing is located on chromosome 11p13. Three single nucleotide polymorphisms (SNPs) in ELP4, a gene which neighbors and plays a crucial role in the expression of PAX6, show association in meta-analysis of the four cohorts yielding P values of respectively 4.79 × 10(-6), 3.92 × 10(-6), and 4.88 × 10(-6) which is below the threshold dictated by the most conservative Bonferroni correction (P = 5.2 × 10(-6)).

This study suggests that the ELP4-PAX6 region plays a role in the DA. Further research to confirm this finding is needed.