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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=6.2x10(-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.

SUBMITTER: Macgregor S

PROVIDER: S-EPMC2883339 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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

Macgregor Stuart S Hewitt Alex W AW Hysi Pirro G PG Ruddle Jonathan B JB Medland Sarah E SE Henders Anjali K AK Gordon Scott D SD Andrew Toby T McEvoy Brian B Sanfilippo Paul G PG Carbonaro Francis F Tah Vikas V Li Yi Ju YJ Bennett Sonya L SL Craig Jamie E JE Montgomery Grant W GW Tran-Viet Khanh-Nhat KN Brown Nadean L NL Spector Timothy D TD Martin Nicholas G NG Young Terri L TL Hammond Christopher J CJ Mackey David A DA

Human molecular genetics 20100415 13

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 ...[more]

PMID: 20395239

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Project description:This genome-wide association study (GWAS) was conducted to identify major loci that are significantly associated with carcass weight, and their effects, in order to provide increased understanding of the genetic architecture of carcass weight in Hanwoo. This genome-wide association study identified one major chromosome region ranging from 23 Mb to 25 Mb on chromosome 14 as being associated with carcass weight in Hanwoo. Significant Bonferroni-corrected genome-wide associations (P<1.52×10(-6)) were detected for 6 Single Nucleotide Polymorphic (SNP) loci for carcass weight on chromosome 14. The most significant SNP was BTB-01280026 (P = 4.02×10(-11)), located in the 25 Mb region on Bos taurus autosome 14 (BTA14). The other 5 significant SNPs were Hapmap27934-BTC-065223 (P = 4.04×10(-11)) in 25.2 Mb, BTB-01143580 (P = 6.35×10(-11)) in 24.3 Mb, Hapmap30932-BTC-011225 (P = 5.92×10(-10)) in 24.8 Mb, Hapmap27112-BTC-063342 (P = 5.18×10(-9)) in 25.4 Mb, and Hapmap24414-BTC-073009 (P = 7.38×10(-8)) in 25.4 Mb, all on BTA 14. One SNP (BTB-01143580; P = 6.35×10(-11)) lies independently from the other 5 SNPs. The 5 SNPs that lie together showed a large Linkage disequilibrium (LD) block (block size of 553 kb) with LD coefficients ranging from 0.53 to 0.89 within the block. The most significant SNPs accounted for 6.73% to 10.55% of additive genetic variance, which is quite a large proportion of the total additive genetic variance. The most significant SNP (BTB-01280026; P = 4.02×10(-11)) had 16.96 kg of allele substitution effect, and the second most significant SNP (Hapmap27934-BTC-065223; P = 4.04×10(-11)) had 18.06 kg of effect on carcass weight, which correspond to 44% and 47%, respectively, of the phenotypic standard deviation for carcass weight in Hanwoo cattle. Our results demonstrated that carcass weight was affected by a major Quantitative Trait Locus (QTL) with a large effect and by many SNPs with small effects that are normally distributed.

Dataset Information

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

Publications

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

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