Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, the leading cause of irreversible blindness worldwide. IOP is also the only modifiable risk factor for glaucoma. Previous genome-wide association studies have established the contribution of common genetic variants to IOP. The role of rare variants for IOP was unknown. Using whole exome sequencing data from 110,260 participants in the UK Biobank (UKB), we conducted the largest exome-wide association study of IOP to date. In addition to confirming known IOP genes, we identified 40 novel rare-variant genes for IOP, such as BOD1L1, ACAD10 and HLA-B, demonstrating the power of including and aggregating rare variants in gene discovery. About half of these IOP genes are also associated with glaucoma phenotypes in UKB and the FinnGen cohort. Six of these genes, i.e. ADRB1, PTPRB, RPL26, RPL10A, EGLN2, and MTOR, are drug targets that are either established for clinical treatment or in clinical trials. Furthermore, we constructed a rare-variant polygenic risk score and showed its significant association with glaucoma in independent participants (n = 312,825). We demonstrated the value of rare variants to enhance our understanding of the biological mechanisms regulating IOP and uncovered potential therapeutic targets for glaucoma.

升高的眼内压 (IOP) 是青光眼的主要危险因素，青光眼是全世界不可逆失明的主要原因。IOP 也是青光眼唯一可改变的危险因素。以前的全基因组关联研究已经确定了常见遗传变异对 IOP 的贡献。IOP 罕见变异的作用尚不清楚。使用来自英国生物银行 (UKB) 110,260 名参与者的全外显子组测序数据，我们进行了迄今为止最大的 IOP 全外显子组关联研究。除了确认已知的 IOP 基因外，我们还鉴定了 40 个新的 IOP 罕见变异基因，例如BOD1L1、ACAD10和HLA-B，展示了在基因发现中包含和聚集稀有变体的力量。这些 IOP 基因中约有一半也与 UKB 和 FinnGen 队列中的青光眼表型相关。这些基因中的六个，即ADRB1、PTPRB、RPL26、RPL10A、EGLN2和MTOR，是为临床治疗或临床试验建立的药物靶标。此外，我们构建了一个罕见变异的多基因风险评分，并在独立参与者 (n = 312,825) 中显示其与青光眼的显着相关性。我们展示了罕见变异的价值，以增强我们对调节 IOP 的生物学机制的理解，并发现了青光眼的潜在治疗靶点。