Publications by authors named "Janey L Wiggs"

169 Publications

Identification of Estrogen Signaling in a Prioritization Study of Intraocular Pressure-Associated Genes.

Int J Mol Sci 2021 Sep 24;22(19). Epub 2021 Sep 24.

Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA.

Elevated intraocular pressure (IOP) is the only modifiable risk factor for primary open-angle glaucoma (POAG). Herein we sought to prioritize a set of previously identified IOP-associated genes using novel and previously published datasets. We identified several genes for future study, including several involved in cytoskeletal/extracellular matrix reorganization, cell adhesion, angiogenesis, and TGF-β signaling. Our differential correlation analysis of IOP-associated genes identified 295 pairs of 201 genes with differential correlation. Pathway analysis identified β-estradiol as the top upstream regulator of these genes with mediating 25 interactions. Several genes (i.e., , , and ) regulated by β-estradiol/ were highly expressed in non-glaucomatous human trabecular meshwork (TM) or Schlemm's canal (SC) cells and specifically expressed in TM/SC cell clusters defined by single-cell RNA-sequencing. We confirmed gene and protein expression in human TM cells and TM/SC tissue with quantitative real-time PCR and immunofluorescence, respectively. 17β-estradiol was identified in bovine, porcine, and human aqueous humor (AH) using ELISA. In conclusion, we have identified estrogen receptor signaling as a key modulator of several IOP-associated genes. The expression of ESR1 and these IOP-associated genes in TM/SC tissue and the presence of 17β-estradiol in AH supports a role for estrogen signaling in IOP regulation.
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http://dx.doi.org/10.3390/ijms221910288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508848PMC
September 2021

Juvenile-onset Open-angle Glaucoma - A Clinical and Genetic Update.

Surv Ophthalmol 2021 Sep 15. Epub 2021 Sep 15.

Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. Electronic address:

Juvenile-onset open-angle glaucoma (JOAG) is a subset of primary open-angle glaucoma that is diagnosed before 40 years of age. The disease may be familial or non-familial, with proportions varying among different populations. Myocilin mutations are the most commonly associated. JOAG is characterized by high intraocular pressures (IOP), with many patients needing surgery. The mean age at diagnosis is in the 3 decade, with a male preponderance. Myopia is a common association. The pathophysiology underlying the disease is immaturity of the conventional outflow pathways, which may or may not be observed on gonioscopy and anterior segment optical coherence tomography. The unique optic nerve head features include large discs with deep, steep cupping associated with high IOP-induced damage. Progression rates among JOAG patients are comparable to adult primary glaucomas, but as the disease affects younger patients, the projected disability from this disease is higher. Early diagnosis, prompt management, and life-long monitoring play an important role in preventing disease progression. Gene-based therapies currently under investigation offer future hope.
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http://dx.doi.org/10.1016/j.survophthal.2021.09.001DOI Listing
September 2021

Development of Primary Open Angle Glaucoma-Like Features in a Rhesus Macaque Colony From Southern China.

Transl Vis Sci Technol 2021 08;10(9):20

PriMed Non-human Primate Research Center of Sichuan PriMed Shines Bio-tech Co., Ltd., Ya'an, Sichuan Province, China.

Purpose: To describe the ocular phenotype of spontaneous glaucoma in a non-human primate colony.

Methods: In total, 722 Rhesus macaque monkeys aged 10 to 25 years underwent optical coherence tomography (OCT), fundus photography (FP), and intraocular pressure (IOP) measurements. Monkeys with baseline cup-to-disc ratio (CDR) <0.5 were used to establish baseline ocular features. A subset was followed longitudinally for three years and compared to glaucoma suspects on the basis of OCT/FP criteria.

Results: The average IOP under ketamine sedation and average CDR for the entire colony was 13.0 ± 4.3 mm Hg and 0.38 ± 0.07, respectively. The mean baseline conscious IOP of glaucoma suspects (N = 18) versus controls (N = 108) was 16.2 ± 3.5 mm Hg and 13.9 ± 2.3 mm Hg, respectively (P = 0.001). All glaucoma suspects had unremarkable slit lamp examinations and open angles based on anterior segment OCT. Baseline global circumpapillary retinal nerve fiber layer (RNFL) thickness was 91.5 ± 11.0 µM versus 102.7 ± 8.5 µM in suspects and controls, respectively (P < 0.0001). All sectors on the baseline circumpapillary OCT showed a significant reduction in RNFL thickness versus controls (P ≤ 0.0022) except for the temporal sector (P ≥ 0.07). In three-year longitudinal analysis, neither CDR nor OCT parameters changed in controls (N = 40; P ≥ 0.16), whereas significant increase in CDR (P = 0.018) and nominally significant decreases in two OCT sectors (nasal, P = 0.023 and nasal inferior, P = 0.046) were noted in suspects.

Conclusions: Members of a nonhuman primate colony exhibit important ophthalmic features of human primary open-angle glaucoma.

Translational Relevance: Identification of a spontaneous model of glaucoma in nonhuman primates represents an unprecedented opportunity to elucidate the natural history, pathogenesis and effective therapeutic strategies for the disease.
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http://dx.doi.org/10.1167/tvst.10.9.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374995PMC
August 2021

Prospective study of dietary intake of branched-chain amino acids and the risk of primary open-angle glaucoma.

Acta Ophthalmol 2021 Jul 8. Epub 2021 Jul 8.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Purpose: Metabolomic and preclinical studies suggest that branched-chain amino acids (BCAA) may be inversely associated with neurodegenerative diseases including glaucoma. We therefore assessed the long-term association between dietary intake of BCAA and incident primary open-angle glaucoma (POAG) and POAG subtypes.

Methods: We followed biennially participants of the Nurses' Health Study (NHS; 65 531 women: 1984-2016), Health Professionals Follow-up Study (42 254 men: 1986-2016) and NHSII (66 904 women; 1991-2017). Eligible participants were 40+ years old and reported eye examinations. Repeated validated food frequency questionnaires were used to assess dietary intake of BCAA. Incident cases of POAG and POAG subtypes defined by visual field (VF) loss and untreated intraocular pressure (IOP) were confirmed by medical record review. Multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.

Results: We identified 1946 incident POAG cases. The pooled MVRRs of POAG for the highest quintile (Q5 = 17.1 g/day) versus lowest quintile (Q1 = 11.2 g/day) of total BCAA intake was 0.93 (95% CI, 0.73-1.19; p  = 0.45; p  = 0.24). For subtypes of POAG defined by IOP level or POAG with only peripheral VF loss, no associations were observed for men or women (p  ≥ 0.20); however, for the POAG subtype with early paracentral VF loss, there was a suggestion of an inverse association in women (MVRR  = 0.80 [95% CI, 0.57-1.12; p  = 0.12]) but not in men (MVRR  = 1.38 [95% CI, 0.81-2.34; p  = 0.28; p  = 0.06]).

Conclusion: Higher dietary intake of BCAA was not associated with POAG risk.
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http://dx.doi.org/10.1111/aos.14971DOI Listing
July 2021

Exome-based investigation of the genetic basis of human pigmentary glaucoma.

BMC Genomics 2021 Jun 26;22(1):477. Epub 2021 Jun 26.

Department of Ophthalmology and Visual Sciences, Carver College of Medicine, 3111B Medical Education and Research Facility, University of Iowa, 375 Newton Road, Iowa City, IA52245, USA.

Background: Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause PDS by testing cohorts of patients and controls for mutations using a tiered analysis of exome data.

Results: Our primary analysis evaluated melanosome-related genes that cause dispersion of iris pigment in mice (TYRP1, GPNMB, LYST, DCT, and MITF). We identified rare mutations, but they were not statistically enriched in PDS patients. Our secondary analyses examined PMEL (previously linked with PDS), MRAP, and 19 other genes. Four MRAP mutations were identified in PDS cases but not in controls (p = 0.016). Immunohistochemical analysis of human donor eyes revealed abundant MRAP protein in the iris, the source of pigment in PDS. However, analysis of MRAP in additional cohorts (415 cases and 1645 controls) did not support an association with PDS. We also did not confirm a link between PMEL and PDS in our cohorts due to lack of reported mutations and similar frequency of the variants in PDS patients as in control subjects.

Conclusions: We did not detect a statistical enrichment of mutations in melanosome-related genes in human PDS patients and we found conflicting data about the likely pathogenicity of MRAP mutations. PDS may have a complex genetic basis that is not easily unraveled with exome analyses.
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http://dx.doi.org/10.1186/s12864-021-07782-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235805PMC
June 2021

The Heritability of Primary Angle Closure Anatomic Traits and Predictors of Angle Closure in South Indian Siblings.

Am J Ophthalmol 2021 May 13;230:188-199. Epub 2021 May 13.

Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Purpose: To estimate the heritability of ocular biometric and anterior chamber morphologic parameters and to determine predictors of angle closure concordance in South Indian probands with angle closure and their siblings DESIGN: Prospective observational cohort study METHODS: Subjects received a standardized ophthalmic examination, A-scan ultrasonography, pachymetry, and anterior segment optical coherence tomography (ASOCT) imaging. Heritability was calculated using residual correlation coefficients adjusted for age, sex, and home setting. Concordant sibling pairs were defined as both proband and sibling with angle closure. Predictors of angle closure concordance among siblings were calculated using multivariable logistic regression models.

Results: A total of 345 sibling pairs participated. All anterior chamber parameters were highly heritable (P < .001 for all). Similarly, all iris parameters, axial length, lens thickness (LT), central corneal thickness, anterior lens curvature, lens vault (LV), spherical equivalent, and intraocular pressure were moderately to highly heritable (P < .004 for all). LV and LT were more heritable among concordant siblings (P < .05 for both). In contrast, ASOCT angle parameters had statistically insignificant heritability estimates. In multivariable analyses, siblings older than their probands were more likely to be concordant for angle closure (OR 1.05, 95% CI 1.01, 1.09; P = .02) and siblings with deeper anterior chamber depths (ACDs) compared to their proband were less likely to be concordant for angle closure (OR 0.74, 95% CI 0.64, 0.86; P < .001).

Conclusions: Iris, anterior chamber, and lens parameters may be heritable whereas angle parameters were not. LT and LV may play important roles in the pathogenesis of angle closure. Siblings who are older or have a shallower ACD may need more careful disease monitoring.
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http://dx.doi.org/10.1016/j.ajo.2021.04.038DOI Listing
May 2021

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

PLoS Genet 2021 05 12;17(5):e1009497. Epub 2021 May 12.

School of Life Course Sciences, Section of Ophthalmology, King's College London, London, United Kingdom.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.
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http://dx.doi.org/10.1371/journal.pgen.1009497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143408PMC
May 2021

DNAJC30 biallelic mutations extend mitochondrial complex I-deficient phenotypes to include recessive Leber's hereditary optic neuropathy.

Authors:
Janey L Wiggs

J Clin Invest 2021 03;131(6)

Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease and in most cases is caused by mutations in mitochondrial DNA-encoded (mtDNA-encoded) respiratory complex I subunit ND1, ND4, or ND6. In this issue of the JCI, Stenton et al. describe biallelic mutations in a nuclear DNA-encoded gene, DNAJC30, establishing recessively inherited LHON (arLHON). Functional studies suggest that DNAJC30 is a protein chaperone required for exchange of damaged complex I subunits. Hallmark mtDNA LHON features were also found in arLHON, including incomplete penetrance, male predominance, and positive response to idebenone therapy. These results extend complex I-deficient phenotypes to include recessively inherited optic neuropathy, with important clinical implications for genetic counseling and therapeutic considerations.
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http://dx.doi.org/10.1172/JCI147734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954582PMC
March 2021

Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank.

Ophthalmology 2021 Sep 10;128(9):1300-1311. Epub 2021 Mar 10.

Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Ocular Genomics Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population.

Design: Cross-sectional population-based study.

Participants: Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs).

Methods: A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG).

Main Outcome Measures: Penetrance of glaucoma.

Results: Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). Of those with DDG, 31% self-reported or had International Classification of Diseases codes for glaucoma, whereas 69% were undiagnosed. Those with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (P < 0.001) vs. those without glaucoma. This difference in IOPcc was larger in those with DDG with a prior glaucoma diagnosis versus those not diagnosed (P < 0.001). Most p.Gln368Ter carriers showed IOP in the normal range (≤21 mmHg), although this proportion was lower in those with DDG (P < 0.02) and those with prior glaucoma diagnosis (P < 0.03). Prevalence of DDG increased with each decile of POAG PRS. Individuals with DDG demonstrated significantly higher PRS compared with those without glaucoma (0.37 ± 0.97 vs. 0.01 ± 0.90; P = 0.03). Of those with DDG, individuals with a prior diagnosis of glaucoma had higher PRS compared with undiagnosed individuals (1.31 ± 0.64 vs. 0.00 ± 0.81; P < 0.001) and 27.5 times (95% confidence interval, 2.5-306.6) adjusted odds of being in the top decile of PRS for POAG.

Conclusions: One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.
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http://dx.doi.org/10.1016/j.ophtha.2021.03.007DOI Listing
September 2021

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Nat Commun 2021 02 24;12(1):1258. Epub 2021 Feb 24.

Faculty of Medicine, University of Southampton, Southampton, UK.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
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http://dx.doi.org/10.1038/s41467-020-20851-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904932PMC
February 2021

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

JAMA 2021 02;325(8):753-764

Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

The GGLEAM Study: Understanding Glaucoma in the Ohio Amish.

Int J Environ Res Public Health 2021 02 6;18(4). Epub 2021 Feb 6.

Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.

Glaucoma leads to millions of cases of visual impairment and blindness around the world. Its susceptibility is shaped by both environmental and genetic risk factors. Although over 120 risk loci have been identified for glaucoma, a large portion of its heritability is still unexplained. Here we describe the foundation of the Genetics of GLaucoma Evaluation in the AMish (GGLEAM) study to investigate the genetic architecture of glaucoma in the Ohio Amish, which exhibits lower genetic and environmental heterogeneity compared to the general population. To date, we have enrolled 81 Amish individuals in our study from Holmes County, Ohio. As a part of our enrollment process, 62 GGLEAM study participants (42 glaucoma-affected and 20 unaffected individuals) received comprehensive eye examinations and glaucoma evaluations. Using the data from the Anabaptist Genealogy Database, we found that 80 of the GGLEAM study participants were related to one another through a large, multigenerational pedigree containing 1586 people. We plan to integrate the health and kinship data obtained for the GGLEAM study to interrogate glaucoma genetics and pathophysiology in this unique population.
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http://dx.doi.org/10.3390/ijerph18041551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915874PMC
February 2021

Intraocular Pressure, Glaucoma, and Dietary Caffeine Consumption: A Gene-Diet Interaction Study from the UK Biobank.

Ophthalmology 2021 06 14;128(6):866-876. Epub 2020 Dec 14.

Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York.

Purpose: We examined the association of habitual caffeine intake with intraocular pressure (IOP) and glaucoma and whether genetic predisposition to higher IOP modified these associations. We also assessed whether genetic predisposition to higher coffee consumption was related to IOP.

Design: Cross-sectional study in the UK Biobank.

Participants: We included 121 374 participants (baseline ages, 39-73 years) with data on coffee and tea intake (collected 2006-2010) and corneal-compensated IOP measurements in 2009. In a subset of 77 906 participants with up to 5 web-based 24-hour-recall food frequency questionnaires (2009-2012), we evaluated total caffeine intake. We also assessed the same relationships with glaucoma (9286 cases and 189 763 controls).

Methods: We evaluated multivariable-adjusted associations with IOP using linear regression and with glaucoma using logistic regression. For both outcomes, we examined gene-diet interactions using a polygenic risk score (PRS) that combined the effects of 111 genetic variants associated with IOP. We also performed Mendelian randomization using 8 genetic variants associated with coffee intake to assess potential causal effects of coffee consumption on IOP.

Main Outcome Measures: Intraocular pressure and glaucoma.

Results: Mendelian randomization analysis did not support a causal effect of coffee drinking on IOP (P > 0.1). Greater caffeine intake was associated weakly with lower IOP: the highest (≥232 mg/day) versus lowest (<87 mg/day) caffeine consumption was associated with a 0.10-mmHg lower IOP (P = 0.01). However, the IOP PRS modified this association: among those in the highest IOP PRS quartile, consuming > 480 mg/day versus < 80 mg/day was associated with a 0.35-mmHg higher IOP (P = 0.01). The relationship between caffeine intake and glaucoma was null (P ≥ 0.1). However, the IOP PRS also modified this relationship: compared with those in the lowest IOP PRS quartile consuming no caffeine, those in the highest IOP PRS quartile consuming ≥ 321 mg/day showed a 3.90-fold higher glaucoma prevalence (P = 0.0003).

Conclusions: Habitual caffeine consumption was associated weakly with lower IOP, and the association between caffeine consumption and glaucoma was null. However, among participants with the strongest genetic predisposition to elevated IOP, greater caffeine consumption was associated with higher IOP and higher glaucoma prevalence.
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http://dx.doi.org/10.1016/j.ophtha.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154631PMC
June 2021

Association of APOE With Primary Open-Angle Glaucoma Suggests a Protective Effect for APOE ε4.

Invest Ophthalmol Vis Sci 2020 07;61(8)

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Purpose: Prior studies have demonstrated that microglial activation is involved in the pathogenesis of primary open-angle glaucoma (POAG). Here we sought to identify genetic associations between POAG and variants in APOE and TREM2, genes associated with Alzheimer disease (AD) that critically regulate microglial neurodegeneration-associated molecular signature.

Methods: APOE genotypes were called using imputed data from the NEIGHBOR consortium (2120 POAG cases, 2262 controls) and a second cohort from the Massachusetts Eye and Ear Infirmary (MEEI; 486 cases, 344 controls). TREM2 coding variants were genotyped by means of the Illumina HumanExome BeadArray. The data set was analyzed for association with POAG overall, as well as the high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) subgroups, using logistic regression adjusting for age and sex.

Results: In the combined NEIGHBOR-MEEI data set, significant association was observed for APOE ε4 in POAG overall (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.74-0.94; P = 0.0022) and in both the HTG subgroup (OR, 0.81; 95% CI, 0.70-0.94; P = 0.0052) and NTG subgroup (OR, 0.71; 95% CI, 0.58-0.87; P = 0.0014). A rare TREM2 variant (A105V) was found only in HTG cases (3 of 2863 cases) and in none of the controls (P = 0.03). Three TREM2 rare variants associated with AD were not significantly associated with POAG (P > 0.05).

Conclusions: We have found that the APOE ε4 allele is associated with a reduced risk of POAG. Interestingly, the same allele is adversely associated with AD, suggesting a mechanistic difference between neurodegenerative diseases of the eye and the brain. TREM2 variants associated with AD did not significantly contribute to POAG risk.
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http://dx.doi.org/10.1167/iovs.61.8.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425753PMC
July 2020

Cohort Study of Nonmelanoma Skin Cancer and the Risk of Exfoliation Glaucoma.

J Glaucoma 2020 06;29(6):448-455

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital.

Precis: In a cohort study of 120,307 participants with 25+ years of follow-up, a history of nonmelanoma skin cancer (NMSC) was associated with a 40% higher exfoliation glaucoma (XFG) risk.

Purpose: The purpose of this study was to evaluate the relationship between NMSC (a marker of ultraviolet radiation exposure) and XFG.

Methods: We performed a cohort study of US women (n=79,102; 1980-2014) and men (n=41,205; 1986-2014), aged 40+ years and at risk for glaucoma who reported eye examinations. From 1984 (women)/1988 (men), we asked about basal cell carcinoma or squamous cell carcinoma history separately; in prior years, we asked about any NMSC history in a single question. Squamous cell carcinoma was confirmed with histopathology reports while basal cell carcinoma and any early (<1984/<1988) NMSC history was self-reported. Incident XFG cases (362 women and 83 men) were confirmed with medical records. Using pooled data, we estimated multivariable-adjusted relative risks [MVRRs; 95% confidence intervals (CIs)] with Cox proportional hazards models that were stratified by age (in mo), 2-year time period at risk and average lifetime residential latitude.

Results: In multivariable-adjusted analyses, we observed a 40% higher XFG risk with any NMSC history (MVRR=1.40; 95% CI=1.08-1.82); the association was observed even with 4 and 8-year lags in NMSC history. Also, the NMSC association was stronger in younger (below 65 y; MVRR=2.56; 95% CI=1.62-4.05) versus older participants (65 y and above; MVRR=1.25; 95% CI=0.94-1.66; P for interaction=0.01) and those living in the northern latitudes (≥42°N; MVRR=1.92; 95% CI=1.28-2.88) versus more southern latitudes (<42°N; MVRR=1.19; 95% CI=0.86-1.66; P for interaction=0.04).

Conclusion: NMSC was associated with higher XFG risk, particularly among younger participants and those living in the Northern US.
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http://dx.doi.org/10.1097/IJG.0000000000001496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317065PMC
June 2020

Association of the CAV1-CAV2 locus with normal-tension glaucoma in Chinese and Japanese.

Clin Exp Ophthalmol 2020 07 24;48(5):658-665. Epub 2020 Mar 24.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.

Background: The CAV1-CAV2 locus has been associated with primary open-angle glaucoma (POAG) and intraocular pressure. However, its association with normal-tension glaucoma (NTG) was inconclusive. Therefore, we evaluated this association in Chinese and Japanese.

Methods: Two single-nucleotide polymorphisms (SNPs, rs4236601 and rs1052990) from previous genome-wide association studies of POAG were genotyped in a total of 2220 study subjects: a Hong Kong Chinese cohort of 537 NTG patients and 490 controls, a Shantou Chinese cohort of 102 NTG and 731 controls and an Osaka Japanese cohort of 153 NTG and 207 controls. Subgroup analysis by gender was conducted. Outcomes from different cohorts were combined using meta-analysis.

Results: SNP rs4236601 was significantly associated with NTG in the two Chinese cohorts (P = .0019, OR = 4.55, I = 0). In contrast, rs4236601 was monomorphic in the Osaka cohort. The association of rs1052990 was insignificant in a meta-analysis combining Chinese and Japanese cohorts (P = .81, OR = 1.05; I = 64%), and the OR tended towards opposite directions between Chinese (OR = 1.26) and Japanese (OR = 0.69). Gender-specific effects of the SNPs were not statistically significant in the logistic regression or Breslow-day tests of ORs (P > .05), although rs4236601 was significant in males (P = .0068; OR = 10.30) but not in females (P = .14; OR = 2.65) in the meta-analysis of Chinese subjects.

Conclusions: In this study, we confirmed the association of rs4236601 at the CAV1-CAV2 locus with NTG in Chinese. SNP rs4236601 is monomorphic, and rs1052990 tends towards a different direction in the Japanese cohort. Further studies are warranted to verify the ethnic difference and gender-specific effects of this locus.
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http://dx.doi.org/10.1111/ceo.13744DOI Listing
July 2020

Low-carbohydrate-diet scores and the risk of primary open-angle glaucoma: data from three US cohorts.

Eye (Lond) 2020 08 2;34(8):1465-1475. Epub 2020 Mar 2.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Background/objectives: To assess the long-term association between low-carbohydrate dietary patterns and incident primary open-angle glaucoma (POAG), and POAG subtypes defined by highest untreated intraocular pressure (IOP) and by pattern of visual field (VF) loss at diagnosis.

Subjects/methods: We followed 185,638 participants of three large US prospective cohorts biennially (1976-2016, 1986-2016 and 1991-2017). Deciles of three low-carbohydrate-diet scores were calculated to represent adherence to diets lower in carbohydrate and higher in protein and fat from any source, animal sources or plant sources. We confirmed POAG cases (n = 2112) by medical record review and used Cox proportional hazards models to estimate multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs).

Results: There was no association between the three types of low-carbohydrate-diet scores and POAG: the MVRR for POAG in the highest vs. lowest deciles was 1.13 (95% CI, 0.91-1.39; P = 0.40) for the overall score; 1.10 (95% CI, 0.89-1.35; P = 0.38) for the animal score and 0.96 (95% CI, 0.79-1.18; P = 0.88) for the vegetable score. No differential associations by IOP level was found (P ≥ 0.06). However, the vegetable score showed a suggestive inverse association with early paracentral VF loss (highest vs. lowest decile MVRR = 0.78 [95% CI, 0.55-1.10]; P = 0.12) but not with peripheral VF loss only (MVRR = 1.09 [95% CI, 0.83-1.44]; P = 0.14; P = 0.03).

Conclusions: Low-carbohydrate diets were not associated with risk of POAG. Our data suggested that higher consumption of fat and protein from vegetable sources substituting for carbohydrates was associated with lower risk of the POAG subtype with initial paracentral VF loss.
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http://dx.doi.org/10.1038/s41433-020-0820-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470850PMC
August 2020

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.

Nat Genet 2020 02 20;52(2):160-166. Epub 2020 Jan 20.

Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
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http://dx.doi.org/10.1038/s41588-019-0556-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056672PMC
February 2020

Novel homozygous mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy.

Ophthalmic Genet 2019 12 13;40(6):570-573. Epub 2020 Jan 13.

Boston University School of Medicine, Boston, Massachusetts, USA.

: To describe and distinguish clinical phenotypes with the overlapping feature of optic atrophy caused by distinct mutations in the same gene, OPA3. We report 3 affected siblings in a consanguineous family harboring a novel OPA3 mutation causing 3-methylglutaconic aciduria type III with optic atrophy.: Retrospective case series.: Three siblings (2 male, 1 female) among 6 children in a consanguineous Afghani family developed decreased vision from early childhood. Both parents and all extended family members were unaffected. All 3 affected siblings suffered from severe visual impairment ranging from visual acuities of 20/150 to counting fingers. All had spastic lower extremity weakness and ataxia. Two of the three affected siblings also had a history of seizures, and the female sibling had limited cognition with diffuse atrophic changes on brain MRI. Two of the three individuals also had migraine-like headaches. Urine organic acid analysis revealed mildly elevated 3-methylglutaconic acid for the male siblings. Whole exome sequencing and subsequent PCR confirmation revealed a novel variant in OPA3 (intron1, c.142 + 2_142 + 3dupTG), affecting the consensus sequence of the splice site, for which all 3 clinically affected siblings were homozygous.: Mutations in OPA3 can cause optic atrophy in a dominant pattern of inheritance associated with cataract or in a recessive pattern associated with spastic paresis and ataxia. The novel recessive mutation and clinical presentations described herein further support how different mutation types affecting OPA3 can produce distinct clinical phenotypes and underscore the critical and susceptible role of mitochondrial health in optic nerve function.
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http://dx.doi.org/10.1080/13816810.2019.1711428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050282PMC
December 2019

Childhood glaucoma genes and phenotypes: Focus on FOXC1 mutations causing anterior segment dysgenesis and hearing loss.

Exp Eye Res 2020 01 11;190:107893. Epub 2019 Dec 11.

Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. Electronic address:

Childhood glaucoma is an important cause of blindness world-wide. Eleven genes are currently known to cause inherited forms of glaucoma with onset before age 20. While all the early-onset glaucoma genes cause severe disease, considerable phenotypic variability is observed among mutations carriers. In particular, FOXC1 genetic variants are associated with a broad range of phenotypes including multiple forms of glaucoma and also systemic abnormalities, especially hearing loss. FOXC1 is a member of the forkhead family of transcription factors and is involved in neural crest development necessary for formation of anterior eye structures and also pharyngeal arches that form the middle ear bones. In this study we review the clinical phenotypes reported for known FOXC1 mutations and show that mutations in patients with reported ocular anterior segment abnormalities and hearing loss primarily disrupt the critically important forkhead domain. These results suggest that optimal care for patients affected with anterior segment dysgenesis should include screening for FOXC1 mutations and also testing for hearing loss.
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http://dx.doi.org/10.1016/j.exer.2019.107893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425631PMC
January 2020

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters.

Commun Biol 2019 27;2:435. Epub 2019 Nov 27.

1Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands.

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in and rs1028727 near at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.
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http://dx.doi.org/10.1038/s42003-019-0634-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881308PMC
July 2020

Muir-Torre Syndrome: The Importance of a Detailed Family History.

Case Rep Ophthalmol 2019 May-Aug;10(2):180-185. Epub 2019 May 23.

Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA.

Muir-Torre syndrome, a variant of Lynch syndrome or hereditary nonpolyposis colorectal cancer, is an autosomal dominant disease characterized by skin neoplasms (sebaceous or keratoacanthomas) and visceral malignancies. Due to the rarity of the syndrome there are no firm guidelines on how and when to test patients with its typical skin lesions. We describe a case that highlights the importance of a detailed family history.
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http://dx.doi.org/10.1159/000500662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760355PMC
May 2019

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

JAMA 2019 11;322(17):1682-1691

Clayton Eye Care Center Management Inc, Marrow, Georgia.

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.
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http://dx.doi.org/10.1001/jama.2019.16161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865235PMC
November 2019

Clinical implications of recent advances in primary open-angle glaucoma genetics.

Eye (Lond) 2020 01 23;34(1):29-39. Epub 2019 Oct 23.

NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.

Over the last decade, genetic studies, including genome-wide association studies (GWAS), have accelerated the discovery of genes and genomic regions contributing to primary open-angle glaucoma (POAG), a leading cause of irreversible vision loss. Here, we review the findings of genetic studies of POAG published in English prior to September 2019. In total, 74 genomic regions have been associated at a genome-wide level of significance with POAG susceptibility. Recent POAG GWAS provide not only insight into global and ethnic-specific genetic risk factors for POAG susceptibility across populations of diverse ancestry, but also important functional insights underlying biological mechanisms of glaucoma pathogenesis. In this review, we also summarize the genetic overlap between POAG, glaucoma endophenotypes, such as intraocular pressure and vertical cup-disc ratio (VCDR), and other eye disorders. We also discuss approaches recently developed to increase power for POAG locus discovery and to predict POAG risk. Finally, we discuss the recent development of POAG gene-based therapies and future strategies to treat glaucoma effectively. Understanding the genetic architecture of POAG is essential for an earlier diagnosis of this common eye disorder, predictive testing of at-risk patients, and design of gene-based targeted medical therapies none of which are currently available.
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http://dx.doi.org/10.1038/s41433-019-0632-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002426PMC
January 2020

Association of a Primary Open-Angle Glaucoma Genetic Risk Score With Earlier Age at Diagnosis.

JAMA Ophthalmol 2019 Oct;137(10):1190-1194

Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland.

Importance: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations.

Objective: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis.

Design, Setting, And Participants: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018.

Main Outcomes And Measures: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression.

Results: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4).

Conclusions And Relevance: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.3109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707005PMC
October 2019

Genetic Correlations Between Diabetes and Glaucoma: An Analysis of Continuous and Dichotomous Phenotypes.

Am J Ophthalmol 2019 10 20;206:245-255. Epub 2019 May 20.

Channing Division of Network Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Purpose: A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits.

Design: Cross-sectional study.

Methods: We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure [IOP], central corneal thickness [CCT], corneal hysteresis [CH], corneal resistance factor [CRF], cup-to-disc ratio [CDR], and primary open-angle glaucoma [POAG]). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank, and the International Glaucoma Genetics Consortium. We calculated genetic correlation (r) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT, and select diabetes-related traits based on individual level phenotype data in 2 Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines.

Results: Overall, there was little r between diabetes- and glaucoma-related traits. Specifically, we found a nonsignificant negative correlation between T2D and POAG (r = -0.14; P = .16). Using Sequential Oligogenic Linkage Analysis Routines, the genetic correlations between measured IOP, CCT, FBS, fasting insulin, and hemoglobin A1c were null. In contrast, genetic correlations between IOP and POAG (r ≥ 0.45; P ≤ 3.0 × 10) and between CDR and POAG were high (r = 0.57; P = 2.8 × 10). However, genetic correlations between corneal properties (CCT, CRF, and CH) and POAG were low (r range -0.18 to 0.11) and nonsignificant (P ≥ .07).

Conclusion: These analyses suggest that there is limited genetic correlation between diabetes- and glaucoma-related traits.
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http://dx.doi.org/10.1016/j.ajo.2019.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864262PMC
October 2019

Association of Statin Use and High Serum Cholesterol Levels With Risk of Primary Open-Angle Glaucoma.

JAMA Ophthalmol 2019 07;137(7):756-765

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: The use of statins (hydroxymethylglutaryl coenzyme A inhibitors) has been associated with a lower risk of primary open-angle glaucoma (POAG); however, results have been conflicting, and little is known about the association between high cholesterol levels and POAG.

Objective: To assess the association of elevated cholesterol levels and statin use with incident POAG.

Design, Setting, And Participants: This study used data collected biennially from participants aged 40 years or older who were free of glaucoma and reported eye examinations, within 3 population-based cohorts: the Nurses' Health Study (N = 50 710; followed up from 2000 to 2014), the Nurses' Health Study 2 (N = 62 992; 1999-2015), and the Health Professionals Follow-up Study (N = 23 080; 2000-2014). Incident cases of POAG were confirmed by medical record review. The analyses were performed in January 2019.

Exposures: Biennially updated self-reported information on elevated cholesterol level status, serum cholesterol levels, and duration of statin use.

Main Outcomes And Measures: Multivariable-adjusted relative risks (RRs) and 95% CIs were estimated using Cox proportional hazards regression models on pooled data, with stratification by cohort.

Results: Among the 136 782 participants in the 3 cohorts (113 702 women and 23 080 men), 886 incident cases of POAG were identified. Every 20-mg/dL increase in total serum cholesterol was associated with a 7% increase in risk of POAG (RR, 1.07 [95% CI, 1.02-1.11]; P = .004). Any self-reported history of elevated cholesterol was also associated with a higher risk of POAG (RR, 1.17 [95% CI, 1.00-1.37]). A history of any statin use was associated with a 15% lower risk of POAG (RR, 0.85 [95% CI, 0.73-0.99]). Use of statins for 5 or more years vs never use of statins was associated with a 21% lower risk of POAG (RR, 0.79 [95% CI, 0.65-0.97]; P = .02 for linear trend). The association between use of statins for 5 or more years vs never use of statins and risk of POAG was more inverse in those who were older (≥65 years: RR, 0.70 [95% CI, 0.56-0.87] vs <65 years: RR, 1.05 [95% CI, 0.68-1.63]; P = .01 for interaction).

Conclusions And Relevance: Among adults aged 40 years or older, higher serum cholesterol levels were associated with higher risk of POAG, while 5 or more years of statin use compared with never use of statins was associated with a lower risk of POAG.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.0900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499123PMC
July 2019
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