Rare protein-altering variants in < i > ANGPTL7 < /i > lower intraocular pressure and protect against glaucoma

by Yosuke Tanigawa, Michael Wainberg, Juha Karjalainen, Tuomo Kiiskinen, Guhan Venkataraman, Susanna Lemmel ä, Joni A. Turunen, Robert R. Graham, Aki S. Havulinna, Markus Perola, Aarno Palotie, FinnGen , Mark J. Daly, Manuel A. Rivas Protein-altering variants that are protective against human disease providein vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant inANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP ( β = -0.53 and -0.67 mmHg for heterozygotes, -3.40 and -2.37 mmHg for homozygotes,P = 5.96 x 10−9 and 1.07 x 10−13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify anANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10−12 for all glaucoma type...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research