Genome-wide association identifies ATOH7 as a major gene determining human optic disc size

Abstract

Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P = 6.2 × 10−10, near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P = 3.4 × 10−10. Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P = 1.3 × 10−10 to 4.3 × 10−11, top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P = 1.5 × 10−7, in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P = 0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls.

Expansive marker analysis replicating the association of glaucoma susceptibility with human chromosome loci 1q43 and 10p12.31

“…Recently, several POAG susceptibility loci were identified by genome-wide association (GWA) studies [16][17][18][19][20] and were replicated in multiple ethnicities: 7q31.2 between CAV1 and CAV2, 16,21 9p21.3 with CDKN2B-AS1, 19,20,[22][23][24][25][26] 10q21.3 with ATOH7, 17,18,22,27 and 14q23.1 between SIX1 and SIX6. 17,20,22,28 One of the GWA studies demonstrated the association of POAG with six SNPs that flanked the ZP4, PLXDC2, and TMTC2 genes located at chromosome loci 1q43, 10p12.31, and 12q21.31, respectively, in a Japanese population; 29 however, these associations were not replicated in a South Indian, 30 Afro-Caribbean, 24 or Chinese 31 population.…”

Math5 (Atoh7) gene dosage limits retinal ganglion cell genesis

“…Humans and mice show marked intraspecies variations in the total number of retinal ganglion cells (RGCs) and optic disc area, which are directly correlated measures [1][2][3][4][5]. In principle, this variation may arise from differences in RGC genesis or in the extent of developmental culling.…”

“…disease in humans [15][16][17], with optic nerve aplasia being the primary phenotype in both species. Recent genome-wide association studies (GWAS) have identified the ATOH7 locus as a major determinant of variation in the optic disc area in normal human populations [3][4][5] and a contributing factor in the susceptibility to glaucoma disease [18,19]. However, a substantial cohort of RGCs are Math5-independent, and only a small fraction of Math5+ cells adopt the RGC fate [20].…”

Common and Rare Genetic Risk Factors for Glaucoma

“…Recent genome-wide analyses using normal populations have identified two genes significantly associated with IOP, GAS7 and TMCO1 (van Koolwijk et al 2012). Similar analyses for optic nerve parameters associated with glaucoma risk have identified CDKN2BAS and SIX1SIX6 as genetic risk factors contributing to cup-to-disc-ratio (Ramdas et al 2010;Fan et al 2011) and ATOH7 as an important determinant of optic nerve size (Macgregor et al 2010). Populations from around the world have been used to identify genetic factors contributing to CCT, one of the most heritable of the quantitative ocular traits (Toh et al 2005).…”

“…Additionally, genetic variants associated with quantitative ocular traits that are risk factors for common forms of glaucoma have also been identified. These include IOP (van Koolwijk et al 2012), central corneal thickness (CCT) (Vithana et al 2011;Lu et al 2013), and optic nerve parameters including cup-to-disc ratio and optic nerve area (Ramdas et al 2010;Macgregor et al 2010;Axenovich et al 2011) (Table 3). The clinical features of POAG generally include both elevated IOP and optic nerve degeneration.…”