Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma

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.眼内压（Intraocular pressure, IOP）是原发性开角型青光眼（primary open-angle glaucoma）的高度可遗传危险因素，同时也是当前青光眼治疗的唯一干预靶点。目前，调控眼内压的遗传因素仍未完全明确。本研究针对荷兰4项独立人群队列研究中的11972名参与者，开展了眼内压相关的全基因组关联研究（genome-wide association study）；随后在来自英国、澳大利亚、加拿大以及威康信托病例对照研究联盟2/蓝山眼病研究的4个新增队列的7482名参与者中验证了上述研究结果。研究发现，眼内压与位于17p13.1区域GAS7基因内的rs11656696（p=1.4×10⁻⁸）以及位于1q24.1区域TMCO1基因内的rs7555523（p=1.6×10⁻⁸）存在显著关联。在纳入总计1432例青光眼病例的4项病例对照研究的荟萃分析（meta-analysis）中，这两个变异位点同样表现出与青光眼的关联证据：rs11656696的p值为2.4×10⁻²，rs7555523的p值为9.1×10⁻⁴。GAS7与TMCO1基因在睫状体、小梁网以及筛板、视神经和视网膜中均呈高表达，且二者均可与已知的青光眼致病基因发生功能互作。本研究结果表明，我们已发现两个参与眼内压调控的临床相关基因。