Abstract
The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72×10−19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10−33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10−11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10−10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.
Highlights
The optic nerve head, or optic disc, is the place where the axons of the retinal ganglion cells leave the eye and form the optic nerve.Its morphology, visible by ophthalmoscopy, is important in the diagnosis and follow-up of patients with ophthalmologic diseases, such as ischemic and hereditary optic neuropathies, optic neuritis, papilledema and primary open-angle glaucoma (OAG)
We found evidence for association of three loci with optic disc area: cell division cycle 7 (CDC7)/transforming growth factor beta receptor 3 (TGFBR3) region, atonal homolog 7 (ATOH7), and sal-like 1 (SALL1); and six with vertical cup-disc ratio (VCDR): CDKN2B, SIX1, SCYL1, CHEK2, ATOH7, and doublecortin–like kinase 1 (DCLK1); and one borderline significant locus: breast carcinoma amplified sequence 3 (BCAS3)
Participants who were genotyped and had reliable optic disc data, resulting in a total of 7,360 participants included in the primary genome-wide association studies (GWAS) discovery set
Summary
Study populations The Rotterdam Study I (RS-I) is a prospective population-based cohort study of 7,983 residents aged 55 years and older living in Ommoord, a suburb of Rotterdam, the Netherlands [45]. Baseline examinations for the ophthalmic part took place between 1991 and 1993; follow-up examinations were performed from 1997 to 1999 and from 2002 to 2006. The RS-II and RS-III are two other prospective populationbased cohort studies of 3,011 residents aged 55 years and older and 3,392 residents aged 45 years and older respectively. The rationale and study design are similar to those of the RS-I [45]. The baseline examinations of RS-II took place between 2000 and 2002; follow-up examinations were performed from 2004 to 2005. Baseline examinations of RS-III took place between 2006 and 2009
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