Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data in UK Biobank and FinnGen to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through protein-altering variant association analysis we find a missense variant in UK Biobank (rs28991009 (MAF=0.8%) genotyped in 81,527 individuals with measured IOP and an independent set of 4,269 glaucoma patients and 251,355 controls) that significantly lowers IOP (β = −0.73 mmHg for heterozygotes, −2.96 mmHg for homozygotes, P = 1 × 10 −13 ) and is associated with 34% reduced risk of glaucoma ( P = 0.005). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.1%), which was genotyped in 5,177 glaucoma patients and 130,461 controls and is associated with 30% lower glaucoma risk ( P = 1 × 10 −9 ). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP ( P = 0.002), suggesting the protective mechanism likely resides in the loss of an interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma