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 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 fo

The efficacy of physical exercise interventions on mental health, cognitive function, and ADHD symptoms in children and adolescents with ADHD: an umbrella reviewResearch in context

Summary: Background: A considerable number of published reviews have addressed the effects of physical exercise on mental health, cognitive function, or attention-deficit hyperactivity (ADHD) symptoms as outcomes in children and adolescents with ADHD. Their findings have often conflicted, therefore, there is an urgent need to synthesise a hierarchy of the evidence and examine the credibility of previous meta-analyses. To establish the robustness of these findings, we conducted an additional meta-analysis on a number of individual studies that were not covered in previous reviews but were suitable for inclusion in our own study. Methods: Three reviewers independently searched Web of Science, Psych INFO, Embase, Cochrane Library, PubMed, SPORTDiscus, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) for meta-analyses published between database inceptions to December 1, 2022. The individual studies were also screened from 1 January 2015 to 1 December 2022. We included meta-analyses and eligible individual studies that addressed the effects of exercise on at least one outcome of mental health, cognitive function, or ADHD symptoms in children and adolescents with ADHD. We excluded systematic reviews and articles that lacked sufficient data for a meaningful second analysis. The effect estimates (Hedges’ g), 95% confidence interval (95% CI), 95% prediction interval (95% PI), small study effects, and excess significance bias were calculated. Finally, we categorised the meta-analyses based on the credibility of the evidence criteria and their quality using a Measurement Tool to Assess Systematic Reviews 2 checklist. This umbrella review was registered with PROSPERO, CRD42022361331. Findings: Of 181 listed review articles and 60 individual papers, 10 reviews and 12 individual articles were included in the meta-analyses. This yielded 37 meta-analyses based on 106 study estimates. Evidence was highly suggestive for the effectiveness of exercise (class II) for improving inattention (G = 0.92, 95% CI: 0.44–1.39, 95%), inhibitory control (G = 0.82, 95% CI: 0.52–1.13), and cognitive flexibility (G = 0.52, 95% CI: 0.32–0.72). However, evidence for the effectiveness of exercise on emotional, social, and working memory outcomes was weak, and these results were not significant for hyperactivity and behavioural functioning. Interpretation: Improvement of cognitive flexibility, inhibitory control, and inattention in children and adolescents with ADHD was highly suggested by exercise interventions. However, results were weak for other outcomes (emotional functioning, social functioning, and working memory). Further high-quality randomised controlled trials are, therefore, warranted to determine the effectiveness of exercise on weak outcomes. Funding: None

Evaluation of shared genetic susceptibility to high and low myopia and hyperopia

Importance Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. Objective To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. Design, Setting, and Participants This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. Exposures Four refractive error groups were defined: HM, −6.00 diopters (D) or less; LM, −3.00 to −1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. Main Outcomes and Measures Odds ratios (ORs) of polygenic risk scores in replication samples. Results A total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10−15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10−5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10−7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10−16). Conclusions and Relevance Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM