Gharahkhani, P and Burdon, KP and Hewitt, AW and Law, MH and Souzeau, E and Montgomery, GW and Radford-Smith, G and Mackey, DA and Craig, JE and MacGregor, S, Accurate imputation-based screening of Gln368Ter myocilin variant in primary open-angle glaucoma, Investigative Ophthalmology and Visual Science, 56, (9) pp. 5087-5093. ISSN 0146-0404 (2015) [Refereed Article]
Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.
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.
|Item Type:||Refereed Article|
|Keywords:||primary open-angle glaucoma, MYOC, Gln368Ter, rare variants, imputation|
|Research Division:||Medical and Health Sciences|
|Research Group:||Ophthalmology and Optometry|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Hearing, Vision, Speech and Their Disorders|
|UTAS Author:||Burdon, KP (Professor Kathryn Burdon)|
|UTAS Author:||Hewitt, AW (Professor Alex Hewitt)|
|UTAS Author:||Mackey, DA (Professor David Mackey)|
|Web of Science® Times Cited:||8|
|Deposited By:||Menzies Institute for Medical Research|
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