TY - JOUR
T1 - Genome-wide association identifies ATOH7 as a major gene determining human optic disc size
AU - Macgregor, Stuart
AU - Hewitt, Alex
AU - Hysi, Pirro
AU - Ruddle, Jonathan
AU - Medland, Sarah
AU - Henders, Anjali
AU - Gordon, Scott
AU - Andrew, Toby
AU - McEvoy, Brian
AU - Sanfilippo, Paul
AU - Carbonaro, Francis
AU - Tah, Vikas
AU - Li, Yi
AU - Bennett, Sonya
AU - Craig, Jamie
AU - Montgomery, G
AU - Tran-Viet, Khanh-Nhat
AU - Brown, Nadean
AU - Spector, Tim
AU - Martin, Nicholas
AU - Young, Terri
AU - Hammond, Christopher
AU - Mackey, David
PY - 2010/4/15
Y1 - 2010/4/15
N2 - 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 × 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 × 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 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.
AB - 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 × 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 × 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 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.
UR - http://www.scopus.com/inward/record.url?scp=77954168341&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddq144
DO - 10.1093/hmg/ddq144
M3 - Article
SN - 0964-6906
VL - 19
SP - 2716
EP - 2724
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 13
M1 - ddq144
ER -