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

TitleRare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma.
Publication TypeJournal Article
Year of Publication2020
AuthorsTanigawa, Y, Wainberg, M, Karjalainen, J, Kiiskinen, T, Venkataraman, G, Lemmelä, S, Turunen, JA, Graham, RR, Havulinna, AS, Perola, M, Palotie, A, Daly, MJ, Rivas, MA
Corporate AuthorsFinnGen
JournalPLoS Genet
Date Published2020 05
KeywordsAdult, Aged, Aged, 80 and over, Angiopoietin-like Proteins, Biological Specimen Banks, Case-Control Studies, Cohort Studies, Female, Finland, Gene Frequency, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Glaucoma, Humans, Intraocular Pressure, Loss of Function Mutation, Male, Middle Aged, Mutation, Missense, Polymorphism, Single Nucleotide, United Kingdom

Protein-altering variants that are protective against human disease provide in 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 in ANGPTL7 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 an ANGPTL7 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 types and also protection against its subtypes including exfoliation, primary open-angle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma.

Alternate JournalPLoS Genet
PubMed ID32369491
PubMed Central IDPMC7199928
Grant ListT15 LM007033 / LM / NLM NIH HHS / United States
U01 HG009080 / HG / NHGRI NIH HHS / United States
R01 HG010140 / HG / NHGRI NIH HHS / United States