Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies

Abstract

IMPORTANCE The p.Gln368Ter (rs74315329) risk allele in the myocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom. OBJECTIVES To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT). DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018. MAIN OUTCOMES AND MEASURES The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT. RESULTS A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%. CONCLUSIONS AND RELEVANCE The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.

Risk Stratification and Clinical Utility of Polygenic Risk Scores in Ophthalmology

“…This magnitude of risk was previously only reported for rarer monogenic variants. 43 Gao et al 44 constructed an inclusive PRS using 1691 SNPs associated with IOP using a more lenient statistical threshold (P < 5 × 10 −5 ) and reported a six-fold higher POAG risk in the top quintile relative to the bottom quintile of an internal validation dataset (OR, 6.34 [95% CI, 4. 82-8.33]).…”

“…This magnitude of risk was previously only reported for rarer monogenic variants. 43 Gao et al 44 constructed an inclusive PRS using 1691 SNPs associated with IOP using a more lenient statistical threshold ( P < 5 × 10 −5 ) and reported a six-fold higher POAG risk in the top quintile relative to the bottom quintile of an internal validation dataset (OR, 6.34 [95% CI, 4.82–8.33]). This improved risk prediction can be attributed to a more inclusive SNP selection in the PRS; however, a limitation of this approach was that the test cohort and the GWAS discovery cohort were both from the UK Biobank and thus share geographic, temporal, and methodological properties.…”

An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity

“…10 The most common pathogenic variant in the MYOC gene in individuals of European ancestry (p.Gln368Ter) has a minor allele frequency of 0.13%, yet carries a significant risk of glaucoma with high IOP in those who carry it (in a population based setting odds ratio [OR] = 6.76 with 95% confidence interval [CI] of 4.05-11.29). 11 In family-based studies, the penetrance of p.Gln368Ter to manifest POAG is reported at approximately 80% by the seventh decade of life. 11 IOP in the normal population is a polygenic trait, with recent large genome-wide association studies (GWAS) discovering more than one hundred common loci associated with IOP, accounting for 40% of the heritability.…”

“…11 In family-based studies, the penetrance of p.Gln368Ter to manifest POAG is reported at approximately 80% by the seventh decade of life. 11 IOP in the normal population is a polygenic trait, with recent large genome-wide association studies (GWAS) discovering more than one hundred common loci associated with IOP, accounting for 40% of the heritability. [12][13][14] Khawaja et al reported that these single nucleotide polymorphisms (SNPs) explained 17% of IOP variance in an independent clinical study, and 9% in the UK biobank study which likely reflects the difference in IOP measurement methods.…”

On the use of genetic information in causal inference for human complex diseases: a collection of studies on cancers

“…For the entirety of my candidature, I have also worked on the genetics of other complex traits and outcomes such as addiction, illicit substance use, psychiatric disorders, other malignant cancers and a series of eye-related diseases [156,[339][340][341]. A list of these investigations that were not covered in this thesis was added to Appendix B. I did not expand on any of these projects for several reasons.…”