Accurate Imputation-Based Screening of Gln368Ter Myocilin Variant in Primary Open-Angle Glaucoma

dc.contributor.author Gharahkhani, Puya
dc.contributor.author Burdon, Kathryn Penelope
dc.contributor.author Hewitt, Alex W
dc.contributor.author Law, Matthew H
dc.contributor.author Souzeau, Emmanuelle
dc.contributor.author Montgomery, Grant W
dc.contributor.author Radford-Smith, Graham
dc.contributor.author Mackey, David A
dc.contributor.author Craig, Jamie E
dc.contributor.author MacGregor, Stuart
dc.date.accessioned 2016-02-03T22:55:48Z
dc.date.available 2016-02-03T22:55:48Z
dc.date.issued 2015-08
dc.description Article available freely at PubMed Central (PMC). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525674/ en
dc.description.abstract PURPOSE: Myocilin (MYOC) is a well-established primary open-angle glaucoma (POAG) risk gene, with rare variants known to have high penetrance. The most common clinically relevant risk variant, Gln368Ter, has an allele frequency of 0.1% to 0.3% in populations of European ancestry. Detection of rare MYOC variants has traditionally been conducted using Sanger sequencing. Here we report the use of genotyping arrays and imputation to assess whether rare variants including Gln368Ter can be reliably detected. METHODS: A total of 1155 cases with advanced POAG and 1992 unscreened controls genotyped on common variant arrays participated in this study. Accuracy of imputation of Gln368Ter variants was compared with direct sequencing. A genome-wide association study was performed using additive model adjusted for sex and the first six principal components. RESULTS: We found that although the arrays we used were designed to tag common variants, we could reliably impute the Gln368Ter variant (rs74315329). When tested in 1155 POAG cases and 1992 controls, rs74315329 was strongly associated with risk (odds ratio = 15.53, P = 1.07 × 10-9). All POAG samples underwent full sequencing of the MYOC gene, and we found a sensitivity of 100%, specificity of 99.91%, positive predictive value of 95.65%, and negative predictive value of 100% between imputation and sequencing. Gln368Ter was also accurately imputed in a further set of 1801 individuals without POAG. Among the total set of 3793 (1992 + 1801) individuals without POAG, six were predicted (probability > 95%) to carry the risk variant. CONCLUSIONS: We demonstrate that some clinically important rare variants can be reliably detected using arrays and imputation. These results have important implications for the detection of clinically relevant incidental findings in ongoing and future studies using arrays. en
dc.identifier.citation Gharahkhani P, Burdon KP, Hewitt AW, Law MH, Souzeau E, Montgomery GW, Radford-Smith G, Mackey DA, Craig JE, MacGregor S. (2015) Accurate imputation-based screening of Gln368Ter Myocilin variant in primary open-angle glaucoma. IOVS. 56(9): 5087-93 en
dc.identifier.doi https://doi.org/10.1167/iovs.15-17305 en
dc.identifier.issn 0146-0404
dc.identifier.uri http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525674/
dc.identifier.uri http://hdl.handle.net/2328/35928
dc.language.iso en
dc.publisher Association for Research in Vision and Ophthalmology en
dc.relation http://purl.org/au-research/grants/nhmrc/1023911 en
dc.relation.grantnumber NHMRC/1023911 en
dc.rights Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc. en
dc.rights.holder The Association for Research in Vision and Ophthalmology, Inc. en
dc.title Accurate Imputation-Based Screening of Gln368Ter Myocilin Variant in Primary Open-Angle Glaucoma en
dc.type Article en
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