%0 Journal Article
%A Khawaja, Anthony P
%A Cooke Bailey, Jessica
%A Simcoe, Mark James
%A Igo, Robert P
%A Pasquale, Louis R.
%A Foster, Paul J
%A Wiggs, Janey L
%A Hammond, Christopher J
%A Hysi, Pirro G
%T Genome-wide association study of intraocular pressure identifies 83 novel loci
%B Investigative Ophthalmology & Visual Science
%D 2018
%J Investigative Ophthalmology & Visual Science
%V 59
%N 9
%P 1178-1178
%@ 1552-5783
%X    Raised intraocular pressure (IOP) is the cardinal modifiable risk factor for glaucoma. Previous genome-wide association studies (GWAS) have identified 8 loci associated with IOP. However, together these explain only a small fraction of IOP heritability. We aimed to discover additional loci in the largest GWAS of IOP to date, and to examine the relevance of these loci to disease by testing for association with primary open-angle glaucoma (POAG) in an independent cohort.    In total, 139,555 participants of European descent were included from three cohorts: UK Biobank, EPIC-Norfolk and the previously reported combined results from 14 studies in the International Glaucoma Genetics Consortium (IGGC). Corneal compensated IOP was measured using the Ocular Response Analyzer in UK Biobank and EPIC-Norfolk, and the majority of IGGC studies used Goldmann applanation tonometry. A linear mixed model GWAS for IOP was carried out in UK Biobank and EPIC-Norfolk, and results then meta-analyzed with IGGC. Gene-set enrichment analyses were conducted using MAGENTA. Significant loci from the IOP GWAS were then tested for association with POAG in the NEIGHBORHOOD study (3,853 cases and 33,480 controls) using logistic regression.    There were 112 unique autosomal genomic regions associated with IOP at genome-wide significance (P<5x10-8), 83 of which were novel (not previously associated with IOP, glaucoma or related traits). The strongest novel locus was in DGKG (P= 8.9x10-52). Gene-set enrichment analysis revealed a strong role for angiogenesis (P=7.3x10-5), driven in part by loci in ANGPT1 (P=2.7x10-18) and ANGPT2 (P=1.7x10-13). Other hits included all previously reported IOP-associated loci (including TMCO1 P=2.4x10-87, GAS7 P=4.0x10-68, ABCA1 P=6.2x10-59 and CAV1/CAV2 P=2.5x10-56), known POAG loci (including FOXC1 P=1.8x10-28, TXNRD2 P=5.2x10-12 and ATXN2 P=3.4x10-10) and known primary angle-closure glaucoma loci (PLEKHA7 P=7.2x10-21, FERMT2 P= 7.1x10-13 and GLIS3 P= 1.2x10-10). The majority of the top significant IOP loci were at least nominally associated with POAG in NEIGHBORHOOD.    This analysis has identified a large number of novel genetic loci that underlie IOP regulation. Our results support an important role for angiogenic factors which presumably target Schlemm’s canal, a lymphatic vessel. Additionally, these loci appear to mediate risk for POAG.  This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018. 
%[ 1/20/2021