Common genetic determinants of intraocular pressure and primary open-angle glaucoma

Abstract

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.

Figure 1. Results of the meta-analysis of the gene discovery cohorts.

Figure 2. Regional association plots of the 17p13.1 and 1q24.1 regions in the discovery meta-analysis.

Figure 3. Association of rs11656696 and rs7555523 with glaucoma.

Figure 4. Expression levels of GAS7 and TMCO1 in human ocular tissues.

Quantitative determination of GAS7 and TMCO1 mRNA expression levels in human ocular tissues by using real-time PCR technology (n = 4). The expression levels were normalized against GAPDH and the results are expressed as copynumber/µg RNA. Co, cornea; Tr, trabecular meshwork; Ir, iris; Le, lens; Ci, ciliary body; Re, retina; Ch, choroid; La, lamina cribrosa; Op, optic nerve.

Figure 5. Biochemical and functional interactions between (putative) glaucoma disease genes.

Ingenuity diagram of biochemical and functional interactions between the newly identified GAS7 and TMCO1 disease genes implicated in elevated IOP and glaucoma, and previously known glaucoma disease genes (WDR36, MYOC, OPTN, CAV1). Functional relationships in the knowledge database Ingenuity (www.ingenuity.com) are a compilation of all known gene-relevant biochemical and functional data of in vivo and in vitro experiments involving (molecules, cells and tissues of) rats and mice and man, as well as data from zebrafish and Drosophila and ongoing clinical trials in man. The query genes/proteins GAS7 (including it's drosophila homologue MLL) and TMCO1 are presented in red. Known glaucoma disease genes are given in blue. Blank genes/molecules are generated by the knowledge database to construct a functional network under the criteria specified by the investigator. The diagram was generated using the function “Path Explorer”. In general, solid lines indicate a direct, experimentally verified, physical relationship between two molecules, for example a physical protein-protein interaction, or an enzym-DNA interaction, etc. Dotted lines refer to the existence of an indirect functional relationship, such as co-upregulation in cell cultures under specific experimental conditions. WDR36 = WD Repeat-containing protein 36; OPTN = optineurin; MYOC = myocilin; GAS7 = growth arrest-specific 7; MLL = myeloid/lymphoid or mixed-lineage leukemia; TMCO1 = transmembrane and coiled-coil domains 1; CAV1 = caveolin 1; TGFB1 = transforming growth factor beta 1; CTNNB1 = catenin (cadherin-associated protein) beta 1; RHOA = ras homolog gene family, member A; E2F6 = E2F transcription factor 6; VHL = von Hippel-Lindau; HTT = huntingtin; NOS2 = nitric oxide synthase 2; LOXL1 = lysyl oxidase-like 1; APOE = apolipoprotein E; APP = amyloid beta (A4) precursor protein; CLU = clusterin. As shown, GAS7 (MLL) and TMCO1 interact multiple times and in several ways with previously known glaucoma disease genes. For a specific description of these interactions, see text.