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

Yosuke Tanigawa, Michael Wainberg, Juha Karjalainen, Tuomo Kiiskinen, Guhan Venkataraman, Susanna Lemmelä, Joni A Turunen, Robert R Graham, Aki S Havulinna, Markus Perola, Aarno Palotie, Mark J Daly, Manuel A Rivas, FinnGen, Kimmo Savinainen, Reijo Laaksonen, Jukka Peltola, Airi Jussila, Pia Isomäki, Tarja LaitinenHannu Kankaanranta, Mika Kähönen, Annika Auranen, Hannu Uusitalo, Teea Salmi, Harri Siirtola, Javier Gracia Tabuenca

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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.

Original languageEnglish
Article numbere1008682
JournalPLoS Genetics
Issue number5
Publication statusPublished - 2020
Publication typeA1 Journal article-refereed


  • Adult
  • Aged
  • Aged, 80 and over
  • Angiopoietin-like Proteins/genetics
  • Biological Specimen Banks/statistics & numerical data
  • Case-Control Studies
  • Cohort Studies
  • Female
  • Finland/epidemiology
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetics, Population
  • Genome-Wide Association Study
  • Glaucoma/epidemiology
  • Humans
  • Intraocular Pressure/genetics
  • Loss of Function Mutation/genetics
  • Male
  • Middle Aged
  • Mutation, Missense
  • Polymorphism, Single Nucleotide
  • United Kingdom/epidemiology

Publication forum classification

  • Publication forum level 2


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