advertisement
Abstract #26625 Published in IGR 12-3
Genome-wide association identifies ATOH7 as a major gene determining human optic disc size
Macgregor S; Hewitt AW; Hysi PG; Ruddle JB; Medland SE; Henders AK; Gordon SD; Andrew T; McEvoy B; Sanfilippo PGHuman Molecular Genetics 2010; 19: 2716-2724
Optic nerve assessment is important formany 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, weperformed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P = 6.2 null 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 metaanalysis of the combined data yielding P = 3.4 null 10(-10). Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P = 1.3 null 10(-10) to 4.3 null 10(-11), top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P = 1.5 null 10(-7), in the gene RFTN1.Direct sequencing ofATOH7 in 12 patients withoptic nerve hypoplasia, one of the leadingcauses ofblindness 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, theArg65Gly variantwas found to have very low frequency (0.00066) in an additional set of 672 controls.
D.A. Mackey. Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, 2 Verdun Street, Nedlands, WA 6009, Australia. d.mackey@utas.edu.au
Classification:
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
2.14 Optic disc (Part of: 2 Anatomical structures in glaucoma)
