Rare protein-altering variants in <i>ANGPTL7</i> lower intraocular pressure and protect against glaucoma

Tanigawa, Yosuke; Wainberg, Michael; Karjalainen, Juha; Kiiskinen, Tuomo; Lemmelä, Susanna; Turunen, Joni A.; Graham, Robert; Havulinna, Aki S.; Perola, Markus; Palotie, Aarno; FinnGen,; Daly, Mark J.; Rivas, Manuel A.

doi:10.1101/677443

Cited by 2 publications

(3 citation statements)

References 28 publications

(18 reference statements)

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“…Outlier removal and principal component analysis has been described previously. 18 In SAIGE phenome-wide association analysis, age, sex, 10 principal components, and genotyping batch were used as covariates. 24 Each genotyping batch was included as a covariate for an end point if there were at least 10 cases and 10 controls in that batch to avoid convergence issues.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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IMPORTANCEThe 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 PARTICIPANTSThis 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 MEASURESThe 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 RELEVANCEThis 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.

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Section: Discussionmentioning

confidence: 99%

“…The genotyping and imputation processes of FinnGen are described previously. 18 We used the SAIGE software as developed by Zhou et al 19 for running a phenome-wide association study. SAIGE is a mixed-model logistic regression for R version 3.4.1 (R Project for Statistical Computing) C++ package.…”

Section: Key Pointsmentioning

confidence: 99%

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

et al. 2021

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“…The observation that the retina and optic nerves ofEFEMP1 knockout mice are anatomically normal (McLaughlin et al, 2007;Stanton et al, 2017;Daniel et al, 2020) suggests thatEFEMP1 loss of function also does not underlie glaucoma development. MYOC and EFEMP1 are among a group of proteins expressed in ocular extracellular matrix that also includes Thrombospondin1 (THBS1 ), and Angiopoietin-like 7 (ANGPTL7 ) among other proteins with potential glaucoma involvement (Wirtz et al, 2021;Tanigawa et al, 2020). Although the specific mechanisms underlying the contribution of ECM proteins to glaucoma is not known, preventing mutant MYOC expression (Jain et al, 2017) or encouraging secretion of misfolded myocilin can reduce intraocular pressure in mice (Zode et al, 2011;Zode et al, 2021), and similar approaches may also be therapeutically useful for patients withEFEMP1 mutations.…”

Section: Discussionmentioning

confidence: 99%

EFEMP1 rare variants cause juvenile-onset open angle glaucoma in families from the Philippines

Collantes

Delfin

Fan

et al. 2021

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Juvenile open angle glaucoma (JOAG) is a severe type of glaucoma with childhood onset and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with rare EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cysteine ) co-segregating with disease. Affected variant carriers (N= 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early-onset form of macular degeneration, Malattia Leventinese/Doyne’s Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.

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Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma

Cited by 2 publications

References 28 publications

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

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

EFEMP1 rare variants cause juvenile-onset open angle glaucoma in families from the Philippines

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