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

By Yosuke Tanigawa, Michael Wainberg, Juha Karjalainen, Tuomo Kiiskinen, Susanna Lemmelä, Joni A. Turunen, Robert Graham, Aki Havulinna, Markus Perola, Aarno Palotie, FinnGen, Mark J Daly, Manuel A. Rivas

Posted 26 Jun 2019
bioRxiv DOI: 10.1101/677443 (published DOI: 10.1371/journal.pgen.1008682)

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

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