Analysis of gene mutation spectrum for early-onset high myopia based on whole-exome sequencing.

Do Polygenic Scores Inform Psychiatric Disease Risk After Considering Family History?

10631 Background: Brazil has a highly admixed population with significant Southern European, African and Native American genetic ancestries. Approximately 75% of the population has two or more continental ancestries. Therefore, breast cancer polygenic risk scores (PRS) developed in predominantly European populations requires validation in the Brazilian population. Compared with genotyping arrays and whole genome sequencing, affordable and scalable whole exome sequencing (WES) allows genotyping of both rare and common variants in the targeted regions and imputation of common variants not directly captured. In this study we validate a previously developed 3820-variant PRS using WES in 15,490 Brazilians. Methods: The cohort consisted of 6,362 women with a history of breast cancer (mean age 49.6, stddev 11.6) and 9,128 unphenotyped adults as controls (mean age 41.6, stddev 13.3). WES were performed on germline DNA and variants were called and curated. Imputation was done using the 1000 Genomes Phase 3 reference panel for variants falling outside the WES captured regions. After excluding subjects with known pathogenic or likely pathogenic variants in BRCA1, BRCA2, PALB2, PTEN, or TP53, and first or second-degree relatives of the probands, 14,577 individuals remained in the final analysis (5,730 cases and 8,847 controls). We restricted PRS calculation to 2,893 of the original 3,820 variants with an estimated global imputation accuracy of 96%. Odds ratios (OR) were adjusted using the top 10 principal components. Results: The breast cancer PRS showed a highly significant correlation with cancer risk (p-value = 7.1e-81, OR = 1.43, 95% confidence interval (CI) = 1.38-1.48 per PRS standard deviation). Compared with women in the middle deciles, those in the highest 10% had an OR of 1.93, while those in the lowest 10% had an OR of 0.52 (Table). Conclusions: In this study we show that WES can capture 76% of the variants included in a previously developed and validated breast cancer PRS, and the calculated PRS is correlated with breast cancer risk in the admixed Brazilian population. This opens the door for clinical studies into the application of PRS in Brazil, particularly in women without mutations in breast cancer high-penetrance genes. In addition, our WES-based PRS strategy can be quickly, affordably, and seamlessly adopted by labs that already offer Hereditary Breast Cancer panels that use WES as a backbone. [Table: see text]

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. To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. 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. 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. Odds ratios (ORs) of polygenic risk scores in replication samples. 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). 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.

Stickler syndrome is a connective tissue disorder that affects multiple systems, including the visual system. Seven genes were reported to cause Stickler syndrome in patients with different phenotypes. In this study, we aimed to evaluate the mutation features of the phenotypes of high myopia and retinal detachment. Forty-two probands diagnosed with Stickler syndrome were included. Comprehensive ocular examinations were performed. A targeted gene panel test or whole exome sequencing was used to detect the mutations, and Sanger sequencing was conducted for verification and segregation analysis. Among the 42 probands, 32 (76%) presented with high myopia and 29 (69%), with retinal detachment. Pathogenic mutations were detected in 35 (83%) probands: 27 (64%) probands had COL2A1 mutations, and eight (19%) probands had COL11A1 mutations. Truncational mutations in COL2A1 were present in 21 (78%) probands. Missense mutations in COL2A1 were present in six probands, five of which presented with retinal detachment. De novo COL2A1 mutations were detected in 10 (37%) probands, with a mean paternal childbearing age of 29.64 ± 4.97 years old. The mutation features of probands with high myopia or retinal detachment showed that the probands had a high prevalence of COL2A1 mutations, truncational mutations, and de novo mutations.

Polygenic prediction has yet to make a major clinical breakthrough in precision medicine and psychiatry, where the application of polygenic risk scores is expected to improve clinical decision-making. Most widely used approaches for estimating polygenic risk scores are based on summary statistics from external large-scale genome-wide association studies, which rely on assumptions of matching data distributions. This may hinder the impact of polygenic risk scores in modern diverse populations due to small differences in genetic architectures. Reference-free estimators of polygenic scores are instead based on genomic best linear unbiased predictions and model the population of interest directly. We introduce a framework, named hapla, with a novel algorithm for clustering haplotypes in phased genotype data to estimate heritability and perform reference-free polygenic prediction in complex traits. We utilize inferred haplotype clusters to compute accurate heritability estimates and polygenic scores in a simulation study and the iPSYCH2012 case-cohort for depression disorders and schizophrenia. We demonstrate that our haplotype-based approach robustly outperforms standard genotype-based approaches, which can help pave the way for polygenic risk scores in the future of precision medicine and psychiatry.

The Potential of Current Polygenic Risk Scores to Predict High Myopia and Myopic Macular Degeneration in Multiethnic Singapore Adults

Introduction: This study aimed to investigate the relationship between the age of myopia onset and high myopia and to explore if age of onset mediated the associations of high myopia with parental myopia and time spent on electronics. Methods: This cross-sectional study enrolled 1,118 myopic patients aged 18–40. Information was obtained via a detailed questionnaire. Multivariable logistic regression and linear regression models were utilized to assess age of onset in relation to high myopia and spherical equivalent refractive error, respectively. Structural equation models examined the mediated effect of onset age on the association between parental myopia, time spent on electronics, and high myopia. Results: An early age at myopia onset was negatively correlated with spherical equivalent refractive power. Subjects who developed myopia before the age of 12 were more likely to suffer from high myopia than those who developed myopia after the age of 15. Age of myopia onset was the strongest predictor of high myopia, with an area under the curve in receiver operator characteristic analysis of 0.80. Additionally, the age of myopia onset served as a mediator in the relationships between parental myopia, electronic device usage duration, and the onset of high myopia in adulthood. Conclusions: Age of myopia onset might be the single best predictor for high myopia, and age at onset appeared to mediate the associations of high myopia with parental myopia and time spent on electronics.

Identification of Rare Variants Involved in High Myopia Unraveled by Whole Genome Sequencing

PurposeThe purpose of this study was to develop an Asian polygenic risk score (PRS) to predict high myopia (HM) in Chinese children in the Singapore Cohort of Risk factors for Myopia (SCORM) cohort.MethodsWe included children followed from 6 to 11 years old until teenage years (12–18 years old). Cycloplegic autorefraction, ultrasound biometry, Illumina HumanHap 550, or 550 Duo Beadarrays, demographics, and environmental factors data were obtained. The PRS was generated from the Consortium for Refractive Error and Myopia genomewide association study (n = 542,934) and the Strabismus, Amblyopia, and Refractive Error in Singapore children Study (n = 500). The Growing Up in Singapore Towards healthy Outcomes Cohort study (n = 339) was the replication cohort. The outcome was teenage HM (≤ −5.00 D) with predictive performance assessed using the area under the curve (AUC).ResultsMean baseline age ± SD was 7.85 ± 0.84 (n = 1004) and 571 attended the teenage visit; 23.3% had HM. In multivariate analysis, the PRS was associated with a myopic spherical equivalent with an incremental R2 of 0.041 (95% confidence interval [CI] = 0.010, 0.073; P < 0.001). AUC for HM (0.77 [95% CI = 0.71–0.83]) performed better (P = 0.02) with the PRS compared with a model without (0.72 [95% CI = 0.65, 0.78]). Children at the top 25% PRS risk had a 2.34-fold-greater risk of HM (95% CI = 1.53, 3.55; P < 0.001).ConclusionsThe new Asian PRS improved the predictive performance to detect children at risk of HM.Translational RelevanceClinicians may use the PRS with other predictive factors to identify high risk children and guide interventions to reduce the risk of HM later in life.

Summary: A polygenic risk score (PRS) is a sum of trait-associated alleles across many genetic loci, typically weighted by effect sizes estimated from a genome-wide association study. The application of PRS has grown in recent years as their utility for detecting shared genetic aetiology among traits has become appreciated; PRS can also be used to establish the presence of a genetic signal in underpowered studies, to infer the genetic architecture of a trait, for screening in clinical trials, and can act as a biomarker for a phenotype. Here we present the first dedicated PRS software, PRSice (‘precise'), for calculating, applying, evaluating and plotting the results of PRS. PRSice can calculate PRS at a large number of thresholds (“high resolution”) to provide the best-fit PRS, as well as provide results calculated at broad P-value thresholds, can thin Single Nucleotide Polymorphisms (SNPs) according to linkage disequilibrium and P-value or use all SNPs, handles genotyped and imputed data, can calculate and incorporate ancestry-informative variables, and can apply PRS across multiple traits in a single run. We exemplify the use of PRSice via application to data on schizophrenia, major depressive disorder and smoking, illustrate the importance of identifying the best-fit PRS and estimate a P-value significance threshold for high-resolution PRS studies.Availability and implementation: PRSice is written in R, including wrappers for bash data management scripts and PLINK-1.9 to minimize computational time. PRSice runs as a command-line program with a variety of user-options, and is freely available for download from http://PRSice.infoContact:jack.euesden@kcl.ac.uk or paul.oreilly@kcl.ac.ukSupplementary information:Supplementary data are available at Bioinformatics online.

Polygenic risk score (PRS) has shown promise in predicting prostate cancer (PCa) risk. However, the application of PRS in non-European ancestry was poorly studied. We constructed PRS using 68, 86, or 128 PCa-associated single-nucleotide polymorphisms (SNPs) identified through a large-scale Genome-wide association study (GWAS) in the European ancestry population. A calibration approach was performed to adjust the PRS exact value for each ancestry. The study was conducted in East Asian (ChinaPCa Consortium, n = 2379), European (UK Biobank, n = 209,172), and African American (African Ancestry Prostate Cancer Consortium, n = 6016). Individuals with the highest PRS (in >97.5th percentile) had over 2.5-fold increased risk of PCa than those with average PRS (in 40th-60th percentile) in both European (odds ratio [OR] = 3.79, 95% confidence interval [CI] = 3.46-4.16, p < 0.001) and Chinese (OR = 2.87, 95% CI = 1.29-6.40, p = 0.010), while slightly lower in African American (OR = 1.77, 95% CI = 1.22-2.58, p = 0.008). Compared with the lowest PRS (in <2.5th percentile), increased PRS was also associated with the earlier onset of PCa (All log-rank p < 0.05). The highest PRS contributed to having about 5- to 12-fold higher lifetime risk and 5-10 years earlier at disease onset than the lowest category across different ancestry populations. We demonstrated that European-GWAS-based PRS could also significantly predict PCa risk in Asian ancestry and African ancestry populations.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, often involving a strong genetic background. Polygenic risk scores (PRSs) combine the cumulative effects of multiple genetic variants to quantify an individual’s susceptibility to CVD. Pharmacogenomics (PGx) can further personalize treatment by tailoring medication choices to an individual’s genetic profile. Even with these potential benefits, the extent to which PRS can be integrated into the PGx of CVD remains unclear. Our review provides an overview of current evidence on the application of PRS in the PGx of CVD, examining clinical utility and limitations and providing directions for future research. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews protocol, we conducted a comprehensive literature search in PubMed, EMBASE, and the Web of Science. Studies investigating the relationship between PRS in predicting the efficacy, adverse effects, or cost-effectiveness of cardiovascular medications were selected. Of the 1894 articles identified, 32 met the inclusion criteria. These studies predominantly examined lipid-lowering therapies, antihypertensives, and antiplatelets, although other medication classes (e.g., rate-control drugs, ibuprofen/acetaminophen, diuretics, and antiarrhythmics) were also included. Our findings showed that PRS is most robustly validated in lipid-lowering therapies, especially statins, where studies reported that individuals with higher PRSs derived the greatest reduction in lipids while on statins. Studies analyzing antihypertensives, antiplatelets, and antiarrhythmic medications demonstrated more variable outcomes, though certain PRSs did identify subgroups with significantly improved response rates or a higher risk of adverse events. Though PRS was a strong tool in many cases, we found some key limitations in its applicability in research, such as the under-representation of non-European-ancestry cohorts in the examined studies and a lack of standardized outcome reporting. In conclusion, though PRS offers promise in improving the efficacy of PGx of CVD by enhancing the personalization of medication on an individual level, several obstacles, such as the need for including a broader ancestral diversity and more robust cost-effectiveness data remain. Future research must (i) prioritize validating PRS in ethnically diverse populations, (ii) refine PRS derivation methods to tailor them for drug response phenotypes, and (iii) establish clear and attainable guidelines for standardizing the reporting of outcomes.

PurposeSince high myopia in the younger generation may differ etiologically from high myopia in older generations, we examined whether education-related parameters differ between high myopia in today´s school children and high pathological myopia in today´s elderly generation.MethodsThe investigation included the adult populations of the population-based Beijing Eye Study (BES) (3468 adults;mean age:64.6±9.8years;range:50–93years) and Central India Eye and Medical Study (CIEMS) (4711 adults;age:49.±13.2years;range:30–100years), and the children and teenager populations of the Shandong Children Eye Study (SCES) (6026 children;age:9.7±3.3years;range:4–18years;cycloplegic refractometry), Gobi Desert Children Eye Study (1565;age:11.9±3.5years;range:6–21 years;cycloplegic refractometry), Beijing Pediatric Eye Study (681 children;age:7.7±1.6years;range:5–13 years;non-cycloplegic refractometry,calculation of axial length to corneal curvature radius ratio), Beijing Children Eye Study (15066 children;age:13.2±3.4years;range:7–18years;non-cycloplegic refractometry), Beijing High School Teenager Eye Study (4677 children;age:16.9±0.7years;range:16–18years;non-cycloplegic refractometry).ResultsIn the BES and CIEMS, educational level did not differ significantly between, or was significantly lower in the highly myopic group (myopic refractive error ≥6 diopters) than in the non-highly myopic group. In all non-adult study populations, higher prevalence of high myopia was significantly associated with higher degree of education related parameters such as attendance of high-level schools, and more time spent for indoors near work versus time spent outdoors.ConclusionsComparing associations of old or genetic high myopia in adults with new or acquired high myopia in school children revealed that education-related parameters did not show a clear association with old or genetic high myopia, while in contrast, new high myopia showed strong associations with education. It confirms previous studies that the two forms of high myopia not only differed in age of onset, but also in associations with education as well. The data support the notion of two types of high myopia. Future studies may assess whether the risk of pathologic myopic maculopathy and high myopia associated open-angle glaucoma differs between both types of high myopia.

Polygenic risk scores (PRS) are promising for identifying common variant-related inheritance for psychiatric conditions but their integration into clinical practice depends on their clinical utility and psychiatrists' understanding of PRS. Our online survey explored these issues with 276 professionals working in psychiatric genetics (RR: 19%). Overall, participants demonstrated knowledge of how to interpret PRS results. Their performance on knowledge-based questions was positively correlated with participants' self-reported familiarity with PRS (r = 0.21, p = 0.0006) although differences were not statistically significant (Wald Chi-square = 3.29, df = 1, p = 0.07). However, only 48.9% of all participants answered all knowledge questions correctly. Many participants (56.5%), especially researchers (42%), indicated having at least occasional conversations about the role of genetics in psychiatric conditions with patients and/or family members. Most participants (62.7%) indicated that PRS are not yet sufficiently robust for assessment of susceptibility to schizophrenia; most significant obstacles were low predictive power and lack of population diversity in available PRS (selected, respectively, by 53.6% and 29.3% of participants). Nevertheless, 89.8% of participants were optimistic about the use of PRS in the next 10 years, suggesting a belief that current shortcomings could be addressed. Our findings inform about the perceptions of psychiatric professionals regarding PRS and the application of PRS in psychiatry.

Background The application of polygenic risk score (PRS) in breast cancer (BC) screening presents promising opportunities. Developing recommendations for future use and research on this topic is a key focus of the EU4Health project: Building the EU cancer and public health genomics platform (Can.Heal). We aim to provide these recommendations based on the analysis of available evidence through a transparent and rigorous development process. Methods The recommendations adopt the GRADE evidence to decision methodology, leveraging an evidence review team and a multidisciplinary panel of nine experts. A systematic review is being conducted to evaluate the evidence for PRS in BC screening, in the domains of benefits and harms, acceptability, feasibility, equity and cost-effectiveness. Results Regarding benefits and harms of adding PRS to BC standard screening, we identified 63 relevant articles. Forty-five (71%) discussed benefits, while 14 (22%) addressed harms. Forty-two (67%) were observational studies, 18 (28%) modeling studies and 1 non-randomised control trial (2%) that examined the diagnostic accuracy of PRS-enhanced screening for relative BC risk prediction using measures such as net reclassification index and area under the curve. Lastly, two modeling studies (3%) assessed the clinical utility of PRS-enhanced screening in terms of life years gained, BC deaths averted. The other domains are under examination. The panel convened to redefine the research question and outcomes of interest and will reconvene to assess the certainty of evidence collected, and subsequently to draft recommendations. Conclusions The integration of PRS into BC screening shows potential benefits in improving risk prediction. Ongoing trials, such as Wisdom and MyPEBS, are studying the clinical utility of integrating PRS in BC screening. The approach taken by the Can.Heal aims to ensure that the recommendations are based on a thorough and balanced evaluation of the available evidence. Key messages • The Can.Heal project aims to formulate policy and research recommendations for breast cancer screening using PRS through a thorough evidence review. • Upcoming PRS recommendations rely on expert opinion and modeling studies.