Dataset Information

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration.

ABSTRACT:

Background

High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER.

Methods

The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression.

Findings

In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24).

Interpretation

Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for.

Funding

Supported by the Welsh Government and Fight for Sight (24WG201).

SUBMITTER: Clark R

PROVIDER: S-EPMC10203044 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration.

Clark Rosie R Lee Samantha Sze-Yee SS Du Ran R Wang Yining Y Kneepkens Sander C M SCM Charng Jason J Huang Yu Y Hunter Michael L ML Jiang Chen C Tideman J Willem L JWL Melles Ronald B RB Klaver Caroline C W CCW Mackey David A DA Williams Cathy C Choquet Hélène H Ohno-Matsui Kyoko K Guggenheim Jeremy A JA

EBioMedicine 20230411

<h4>Background</h4>High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER.<h4>Methods</h4>The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiol ...[more]

PMID: 37055258

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Project description:ImportanceMyopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention.ObjectivesTo examine whether genetic information alone can identify children at risk of myopia development and whether including a child's genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia.Design, setting, and participantsMeta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019.Main outcomes and measuresThe primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to -0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to -5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n = 95 619), age of onset of spectacle wear (n = 287 448), and educational attainment (n = 328 917).ResultsA total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P = .02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4-10.9) of high myopia.Conclusions and relevanceA personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87).

Project description:ObjectiveTo summarize relevant evidence investigating the associations between refractive error and age-related macular degeneration (AMD).DesignSystematic review and meta-analysis.MethodsWe searched Medline, Web of Science, and Cochrane databases as well as the reference lists of retrieved articles to identify studies that met the inclusion criteria. Extracted data were combined using a random-effects meta-analysis. Studies that were pertinent to our topic but did not meet the criteria for quantitative analysis were reported in a systematic review instead.Main outcome measuresPooled odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between refractive error (hyperopia, myopia, per-diopter increase in spherical equivalent [SE] toward hyperopia, per-millimeter increase in axial length [AL]) and AMD (early and late, prevalent and incident).ResultsFourteen studies comprising over 5800 patients were eligible. Significant associations were found between hyperopia, myopia, per-diopter increase in SE, per-millimeter increase in AL, and prevalent early AMD. The pooled ORs and 95% CIs were 1.13 (1.06-1.20), 0.75 (0.56-0.94), 1.10 (1.07-1.14), and 0.79 (0.73-0.85), respectively. The per-diopter increase in SE was also significantly associated with early AMD incidence (OR, 1.06; 95% CI, 1.02-1.10). However, no significant association was found between hyperopia or myopia and early AMD incidence. Furthermore, neither prevalent nor incident late AMD was associated with refractive error. Considerable heterogeneity was found among studies investigating the association between myopia and prevalent early AMD (P = 0.001, I2 = 72.2%). Geographic location might play a role; the heterogeneity became non-significant after stratifying these studies into Asian and non-Asian subgroups.ConclusionRefractive error is associated with early AMD but not with late AMD. More large-scale longitudinal studies are needed to further investigate such associations.

Dataset Information

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration.

Background

Methods

Findings

Interpretation

Funding

Publications

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration.

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