Association of the MYOC p.(Gln368Ter) Variant With Glaucoma in a Finnish Population

Abstract

Importance: The c.1102C>T, p.(Gln368Ter) variant in the myocilin (MYOC) gene is a known risk allele for glaucoma. It is the most common MYOC risk variant for glaucoma among individuals of European ancestry, and its prevalence is highest in Finland. Furthermore, exfoliation syndrome has high prevalence in Scandinavia, making the Finnish population ideal to study the association of the variant with different types of glaucoma.

Objectives: To examine the association and penetrance of MYOC p.(Gln368Ter) (rs74315329) variant with different types of glaucoma in a Finnish population.

Design, setting, and participants: This genetic association study included individuals of Finnish ancestry in the FinnGen project. The participants were collected from Finnish biobanks, and the disease end points were defined using nationwide registries. The MYOC c.1102C>T variant was either directly genotyped or imputed with microarrays. Recruitment of samples to FinnGen was initiated in 2017, and data analysis was performed between December 2019 and May 2020.

Main outcomes and measures: The main outcomes were odds ratios (ORs) and penetrance with different types of glaucoma and in different age groups.

Results: A total of 218 792 individuals were included in this study (mean [SD] age 52.4 [17.5] years; 123 579 women [56.5%]), including 8591 (3.9%) with glaucoma, 3412 (1.6%) with primary open-angle glaucoma, 1515 (0.7%) with exfoliation glaucoma, 892 (0.4%) with normal-tension glaucoma, and 4766 (2.2%) with suspected glaucoma. The minor allele frequency of MYOC p.(Gln368Ter) was 0.28%. Individuals with the heterozygous variant had higher odds of primary open-angle glaucoma (OR, 3.36; 95% CI, 2.55-4.37), overall glaucoma (OR, 2.58; 95% CI, 2.12-3.13), suspected glaucoma (OR, 2.53; 95% CI, 1.93-3.26), exfoliation glaucoma (OR, 2.61; 95% CI, 1.60-4.02), and undergoing glaucoma-related operations (OR, 5.45; 95% CI, 2.95-9.28). The penetrance of heterozygous MYOC p.(Gln368Ter) was 5.2% in individuals with primary open-angle glaucoma, 9.6% in individuals with glaucoma, 5.4% in individuals with suspected glaucoma, and 1.9% in individuals with exfoliation glaucoma. There was no significant association with normal-tension glaucoma (OR, 1.69; 95% CI, 0.72-3.35).

Conclusions and relevance: This genetic association study found that the MYOC p.(Gln368Ter) variant was associated with exfoliation glaucoma. The association with normal-tension glaucoma could not be replicated. These findings suggest that MYOC p.(Gln368Ter) was associated with open-angle glaucoma and exfoliation glaucoma in a Finnish population.

Figure.. The Phenome-Wide Association Manhattan Plot of the Myocilin (MYOC) c.1102C>T, p.(Gln368Ter) Variant Across All End Points in FinnGen Data Freeze 5

1 Indicates certain infectious and parasitic diseases; 2, neoplasms from hospital discharges; 3, neoplasms, from cancer register; 4, diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism; 5, endocrine, nutritional and metabolic diseases; 6, diabetes end points; 7, mental and behavioral disorders; 8, psychiatric end points; 9, alcohol-related diseases; 10, diseases of the nervous system; 11, neurological end points; 12, diseases of the eye and adnexa; 13, diseases of the ear and mastoid process; 14, diseases of the circulatory system; 15, cardiometabolic end points; 16, diseases of the respiratory system; 17, asthma and related end points; 18, chronic obstructive pulmonary disorder and related end points; 19, interstitial lung disease end points; 20, diseases of the digestive system; 21, dental end points; 22, gastrointestinal end points; 23, diseases of the skin and subcutaneous tissue; 24, diseases of the musculoskeletal system and connective tissue; 25, rheumatoid end points; 26, diseases of the genitourinary system; 27, pregnancy, childbirth and the puerperium; 28, certain conditions originating in the perinatal period; 29, congenital anomalies, deformations, and chromosomal anomalies; 30, symptoms, signs, and anomalous clinical and laboratory findings, not elsewhere classified; 31, injury, poisoning and certain other consequences of external causes; 32, external causes of morbidity and mortality; 33, factors influencing health status and contact with health services; 34, drug purchase end points; 35, operation end points; 36, diseases marked as autoimmune origin; 37, demonstration end points; 38, other, not yet classified end points (same as miscellaneous); 39, common end point; 40, miscellaneous, not yet classified end points; 41, comorbidity end points.