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

• Published in: Human molecular genetics 2010-07, Vol.19 (13), p.2716-2724
• Main Authors: Macgregor, Stuart, Hewitt, Alex W., Hysi, Pirro G., Ruddle, Jonathan B., Medland, Sarah E., Henders, Anjali K., Gordon, Scott D., Andrew, Toby, McEvoy, Brian, Sanfilippo, Paul G., Carbonaro, Francis, Tah, Vikas, Li, Yi Ju, Bennett, Sonya L., Craig, Jamie E., Montgomery, Grant W., Tran-Viet, Khanh-Nhat, Brown, Nadean L., Spector, Timothy D., Martin, Nicholas G., Young, Terri L., Hammond, Christopher J., Mackey, David A.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Association Studies; Australia; Basic Helix-Loop-Helix Transcription Factors - genetics; Biological and medical sciences; Blindness - genetics; Child; Child, Preschool; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Humans; Membrane Proteins - genetics; Middle Aged; Molecular and cellular biology; Optic Disk; Optic Nerve - pathology; Polymorphism, Single Nucleotide - genetics; Twins; United Kingdom; Young Adult
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddq144

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.