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Editors Selection IGR 9-4

Basic Science: New susceptibility loci for POAG

Comment by Louis Pasquale & Baojian Fan on:

68845 Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma, Khor CC; Do T; Jia H et al., Nature Genetics, 2016; 48: 556-562

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Ethnicity and a positive family history are strong determinants of primary angle-closure glaucoma (PACG), suggesting that genetic factors play a role in this disease. Khor CC et al. report the largest genome-wide association study (GWAS) of PACG to date in a sample totaling 10,503 PACG cases and 29,567 controls from 24 countries. All PACG cases met standardized criteria whose central feature was critical irido-trabecular meshwork apposition without secondary cause. Roughly 40% of cases had a history of acute symptomatology attributable to PACG. In this study, five new genetic loci were significantly associated with PACG: EPDR1 rs3816415, CHAT rs1258267, GLIS3 rs736893, FERMT2 rs7494379, and DPM2-FAM102A rs3739821. The authors provide convincing evidence for replication of these newly discovered loci. Furthermore, significant associations at three previously reported loci at PLEKHA7, COL11A1, and PCMTD1-ST18 were confirmed. The modest effect sizes for all of these variants (odds ratio ~1.2) underscore the genetic complexity for PACG.

None of the PACG gene variants are found in exons, indicating we do not understand how these variants contribute to PACG pathogenesis

Interestingly, all eight loci for PACG identified by GWAS account for only 1.8% of the overall disease variance, indicating significant missing heritability exists - this is a typical result observed for many complex traits.

While the authors demonstrate that the newly discovered gene products are expressed in ocular tissues, none of the PACG gene variants are found in exons, indicating we do not understand how these variants contribute to PACG pathogenesis. Several of the PACG genes (EPDR1, FERMT2 and PLEKHA7) are involved in cell adhesion while CHAT is involved in acetylcholine metabolism. In contrast, known loci for axial length, an endophenotype related to angle closure predisposition, were not associated with PACG in this dataset. We applaud this monumental effort in glaucoma genetics and suspect these findings will open new avenues in exploring glaucoma pathogenesis.

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