Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma
Tuomo T. J. Kiiskinen,
Joni A. Turunen,
Aki S Havulinna,
Manuel A Rivas
Posted 26 Jun 2019
bioRxiv DOI: 10.1101/677443 (published DOI: 10.1371/journal.pgen.1008682)
Posted 26 Jun 2019
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
- Downloaded 919 times
- Download rankings, all-time:
- Site-wide: 22,233
- In genetics: 1,095
- Year to date:
- Site-wide: 50,837
- Since beginning of last month:
- Site-wide: 51,753
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!