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

Publication ,  Journal Article
Macgregor, S; Hewitt, AW; Hysi, PG; Ruddle, JB; Medland, SE; Henders, AK; Gordon, SD; Andrew, T; McEvoy, B; Sanfilippo, PG; Carbonaro, F ...
Published in: Hum Mol Genet
July 1, 2010

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=6.2x10(-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=3.4x10(-10). Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P=1.3x10(-10) to 4.3x10(-11), top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P=1.5x10(-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.

Duke Scholars

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 1, 2010

Volume

19

Issue

13

Start / End Page

2716 / 2724

Location

England

Related Subject Headings

  • Young Adult
  • United Kingdom
  • Twins
  • Polymorphism, Single Nucleotide
  • Optic Nerve
  • Optic Disk
  • Middle Aged
  • Membrane Proteins
  • Humans
  • Genome-Wide Association Study
 

Citation

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Chicago
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Macgregor, S., Hewitt, A. W., Hysi, P. G., Ruddle, J. B., Medland, S. E., Henders, A. K., … Mackey, D. A. (2010). Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet, 19(13), 2716–2724. https://doi.org/10.1093/hmg/ddq144
Macgregor, Stuart, Alex W. Hewitt, Pirro G. Hysi, Jonathan B. Ruddle, Sarah E. Medland, Anjali K. Henders, Scott D. Gordon, et al. “Genome-wide association identifies ATOH7 as a major gene determining human optic disc size.Hum Mol Genet 19, no. 13 (July 1, 2010): 2716–24. https://doi.org/10.1093/hmg/ddq144.
Macgregor S, Hewitt AW, Hysi PG, Ruddle JB, Medland SE, Henders AK, et al. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet. 2010 Jul 1;19(13):2716–24.
Macgregor, Stuart, et al. “Genome-wide association identifies ATOH7 as a major gene determining human optic disc size.Hum Mol Genet, vol. 19, no. 13, July 2010, pp. 2716–24. Pubmed, doi:10.1093/hmg/ddq144.
Macgregor S, Hewitt AW, Hysi PG, Ruddle JB, Medland SE, Henders AK, Gordon SD, Andrew T, McEvoy B, Sanfilippo PG, Carbonaro F, Tah V, Li YJ, Bennett SL, Craig JE, Montgomery GW, Tran-Viet K-N, Brown NL, Spector TD, Martin NG, Young TL, Hammond CJ, Mackey DA. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet. 2010 Jul 1;19(13):2716–2724.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 1, 2010

Volume

19

Issue

13

Start / End Page

2716 / 2724

Location

England

Related Subject Headings

  • Young Adult
  • United Kingdom
  • Twins
  • Polymorphism, Single Nucleotide
  • Optic Nerve
  • Optic Disk
  • Middle Aged
  • Membrane Proteins
  • Humans
  • Genome-Wide Association Study