14 research outputs found
Variation in optineurin (OPTN) allele frequencies between and within populations
PURPOSE: To evaluate the extent to which mutations in the optineurin (OPTN) glaucoma gene play a role in glaucoma in
different populations.
METHODS: Case-controlled study of OPTN sequence variants in individuals with or without glaucoma in populations of
different ancestral origins and evaluate previous OPTN reports. We analyzed 314 subjects with African, Asian, Caucasian
and Hispanic ancestries included 229 cases of primary open-angle glaucoma, 51 cases of juvenile-onset open-angle glaucoma,
33 cases of normal tension glaucoma, and 371 controls. Polymerase chain reaction-amplified OPTN coding exons
were resequenced and case frequencies were compared to frequencies in controls matched for ancestry.
RESULTS: The E50K sequence variant was identified in one individual from Chile with normal tension glaucoma, and the
691_692insAG variant was found in one Ashkenazi Jewish individual from Russia. The R545Q variant was found in two
Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry. In addition to
presenting OPTN allele frequencies for Caucasian and Asian populations that have been the subject of previous reports,
we also present information for populations of Hispanic and black African ancestries.
CONCLUSIONS: Our study contributes additional evidence to support the previously reported association of the OPTN E50K
mutation with glaucoma. After finding an additional 691_692insAG OPTN variant, we can still only conclude that this
variant is rare. Combined analysis of our data with data from more than a dozen other studies indicates no association of
R545Q with glaucoma in most populations. Those same studies disagree in their conclusions regarding the role of M98K
in glaucoma. Our analysis of the combined data provides statistically significant evidence of association of M98K with
normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion
is questionable because of large differences in allele frequencies between and within populations. It is currently not
possible to tell how much of the underlying cause of the allele frequency difference is attributable to demographic, technical, or ascertainment differences among the studies
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Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.
Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies
Novel and known MYOC exon 3 mutations in an admixed Peruvian primary open-angle glaucoma population
Purpose: The aim of this study was to characterize a representative sample of the Peruvian population suffering openangle
glaucoma (OAG) with respect to the myocilin gene (MYOC) mutations, glaucoma phenotype, and ancestry for future
glaucoma risk assessment.
Methods: DNA samples from 414 unrelated Peruvian subjects, including 205 open-angle glaucoma cases (10 juvenile
glaucoma [JOAG], 19 normal-tension glaucoma [NTG], and 176 POAG) and 209 randomly sampled controls, were
screened for nucleotide changes in MYOC exon 3 by conformational sensitive gel electrophoresis (CSGE) and mutation
screening.
Results: We identified a probable causative novel MYOC missense mutation, Gly326Ser, in one POAG case and found
a consistent genotype-phenotype correlation in eight of his relatives. We also found the known causative MYOC mutation
Trp286Arg in one JOAG case and one POAG case. A known causative single base MYOC deletion, T1357, was found in
one POAG case. Two previously reported silent polymorphisms, Thr325Thr and Tyr347Tyr, were found in both the case
and the control populations. A novel missense variant, Met476Arg, was identified in two unrelated controls.
Conclusions: The screening of exon 3 of MYOC in a representative sample of 205 independent POAG patients from Peru
and 209 matched controls identified novel and previously reported mutations (both pathogenic and nonpathogenic) from
other global regions. These results reflect the complex admixture of Amerindian and Old World ancestry in urban
populations of Latin America, in general, and in Peru, in particular. It will be important to gather information about the
ancestral origin of MYOC and other POAG gene mutations to develop screening panels and risk assessment for POAG in
Peru.National Eye Institute, National Institutes
of Health, Bethesda, MD (J.E.R.), Research to Prevent
Blindness (EY011671- J.E.R.), Universidad de San MartĂn de
Porres Funds E10012009016, E10012009011,
E10012009027, E10012012011, Consejo Nacional de
Ciencia y TecnologĂa (Concytec) proyecto OAJ-2003
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Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.
Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 Ă— 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 Ă— 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 Ă— 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 Ă— 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 Ă— 10(-12)). We also confirmed significant association at three previously described loci (P < 5 Ă— 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG
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Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.
Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 Ă— 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 Ă— 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 Ă— 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 Ă— 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 Ă— 10(-12)). We also confirmed significant association at three previously described loci (P < 5 Ă— 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG
Association of genetic variants with primary open-angle glaucoma among individuals with african ancestry
Are there differences in genetic risk factors for primary open-angle glaucoma based on ancestry? FindingsIn this multistage, case-control, genome-wide association study that included 26295 participants, the amyloid-beta A4 precursor protein-binding family B member 2 (APBB2) locus was significantly associated with primary open-angle glaucoma among individuals of African ancestry (odds ratio, 1.19 per copy of the risk allele for single-nucleotide polymorphism rs59892895T>C), but not of European or Asian ancestry. MeaningThis study identified a single-nucleotide polymorphism that demonstrated differential association with primary open-angle glaucoma by ancestry. ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and ParticipantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. ExposuresGenetic variants associated with primary open-angle glaucoma. Main Outcomes and MeasuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as PC) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P=2x10(-8)). The association was validated in an analysis of an additional 6937 affected individuals and 14917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P<.001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P=4x10(-13)). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and RelevanceIn this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies. This genome-wide association study (GWAS) investigates genetic loci associated with primary open-angle glaucoma in individuals in Africa and in the United States with African ancestry.3221716821691FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo10/18353-9; 02/11575-
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Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.
ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, settings, and participantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.ExposuresGenetic variants associated with primary open-angle glaucoma.Main outcomes and measuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data.ResultsA total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and relevanceIn this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies
Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.
Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 Ă— 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 Ă— 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 Ă— 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 Ă— 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 Ă— 10(-12)). We also confirmed significant association at three previously described loci (P < 5 Ă— 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG