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Abstract Leveraging whole genome sequencing data of 1751 individuals from the UK and 2587 Qatari subjects, we suggest here an association of rare variants mapping to the sour taste-associated gene KCNJ2 with reduced low-density lipoprotein cholesterol (LDL-C, P = 2.10 × 10−12) and with a 22% decreased dietary trans-fat intake. This study identifies a novel candidate rare locus for LDL-C, adding insights into the genetic architecture of a complex trait implicated in cardiovascular disease.

Abstract Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.

The evolution of society creates new trends that significantly affect the legal status of public administration, which necessitates an up-to-date study of the accompanying changes. The study therefore aims to analyse the current legal system of Albania and other countries in terms of the impact of legal acts on the entire system of public administration, including local self-government. A set of methods was used in the study, including the analysis, grouping, induction, formal legal and comparative legal approaches. The study identified the overall impact of legal regulation on the entire governance system and society, which was used to formulate specific aspects in which the real interaction of state mechanisms and legal influence takes place. The study analysed the current political and economic situation in Albania, which revealed the main trends in the country’s current strategic directions. Subsequently, the identified directions were studied in detail, which ultimately made it possible to substantiate the importance of the list of strategic legal acts in shaping the development of the entire public administration system. Examples from other countries, such as Germany, the United Kingdom and China, were also used to study this topic, identifying the main differences in the impact of legal regulation on the development of the system under consideration, considering the specific legal, social and economic situation of each country. In addition, the complex also examined the institution of local self-government, which showed how the level of decentralisation of such bodies can affect the success and efficiency of their functioning. In practical terms, this study can be useful for scholars who can deepen their understanding of the dynamics of public administration development and for officials who want to understand the essence of the interaction discussed in the study

Introduction: Vitamin C is an essential nutrient. Sex differences in serum vitamin C concentrations have been observed but are not fully known. Investigation of levels of metabolites may help shed light on how dietary and other environmental exposures interact with molecular processes. O-methylascorbate and ascorbic acid 2-sulfate are two metabolites in the vitamin C metabolic pathway. Past research has found genetic factors that influence the levels of these two metabolites. Therefore, we investigated possible effect modification by sex of genetic variant-metabolite associations and characterized the biological function of these interactions.Methods: We included individuals of European descent from the Canadian Longitudinal Study on Aging with available genetic and metabolic data (n = 9004). We used linear mixed models to tests for genome-wide associations with O-methylascorbate and ascorbic acid 2-sulfate, with and without a sex interaction. We also investigated the biological function of the important genetic variant-sex interactions found for each metabolite.Results: Two genome-wide statistically significant (p value < 5 × 10−8) interaction effects and several suggestive (p value < 10–5) interaction effects were found. These suggestive interaction effects were mapped to several genes including HSD11B2, associated with sex hormones, and AGRP, associated with hunger drive. The genes mapped to O-methylascorbate were differently expressed in the testis tissues, and the genes mapped to ascorbic acid 2-sulfate were differently expressed in stomach tissues.Discussion: By understanding the genetic factors that impact metabolites associated with vitamin C, we can better understand its function in disease risk and the mechanisms behind sex differences in vitamin C concentrations.

Abstract Background Non-surgical periodontal therapy includes not only the local curettage of tartar and bacterial plaque, but also aims to remove "bubbling" bacteria in saliva or gingival fluid, which cause the creation of bacterial plaque and therefore also chronic periodontitis. In the final stage, the indication for giving or not prescribing antibiotics depends on the clinical course of the disease. Probiotics can serve as helpers in the "fight" against the causative pathogenic bacteria, but with the specificity of application in the intermediate stages and not in the final stage of non-surgical periodontal treatment. Main body of the abstract The study is of the review type with the aim of selecting articles published in PubMed in a period of 5 years about the topic of probiotics and their application in non-surgical periodontal therapy for the treatment of chronic periodontitis. The selection of articles was carried out based on the combination of key words. The selected articles were 23 and then classified based on the clinical periodontal parameters that have been studied and the positive, positive/negative or negative attitude about the application or not of probiotics for the treatment of chronic periodontitis as a companion to non-surgical periodontal therapy. Non-concrete well-defined results are observed on the type of dosage and method of application of probiotics, being accompanied by non-concrete results both locally in the affected periodontal areas, but also systemic in the patient's serum. Short conclusion Correct application protocols of probiotics for treatment of chronic periodontitis, but also of other periodontal pathologies, have “the advantage” of avoiding the prescription of systemic antibiotics, in the conditions of increased resistance to them. The effects of probiotics when applied even in the first stages of non-surgical therapy are mainly visible in the reduction of infection inflammation, the most mentioned and most visible results, based on the data published in the literature. More data are required in this regard.

Removable functional appliances (RFA) have long been employed to address Class II malocclusion, particularly in cases involving a significant overjet, a deep bite, and molar class 2 issues. Notably divergent from RFA, myofunctional appliances (PMA) offer several distinct advantages, including applicability in noncompliant patients, adaptability in cases of dental element scarcity, suitability for allergic patients, impression-free utilization, and reduced costs. Within the array of clinical cases treated with PMA, we chose to present an intricate case involving an 8-year-old girl. Our aim was to showcase the immediate effects of PMA and to track the progress over a two-year span. Following one year of PMA treatment, substantial improvements were observed in a large overjet, a deep bite, and lip incompetence—factors often associated with elevated risks of dental trauma. These improvements not only positively impacted dental aesthetics but also engendered normalized nasal respiration and diminished palatal impingement, thereby enhancing the overall quality of life. Upon reaching the two-year mark, the clinical status pertaining to Class II malocclusion remained stable. Further treatment was advised in a subsequent phase to refine imperfections in the dental arch form. Nonetheless, comprehensive data from the prolonged follow-up of patients treated with these appliances are essential to establish robust scientific evidence concerning their long-term efficacy.

Abstract Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Abstract Although glaucoma is a disease modulated by eye pressure, the mechanisms of pressure sensing in the eye are not well understood. Here, we investigated associations between mechanosensitive ion channel gene variants and primary open-angle glaucoma (POAG). Common (minor allele frequency > 5%) single nucleotide polymorphisms located within the genomic regions of 20 mechanosensitive ion channel genes in the K2P, TMEM63, PIEZO and TRP channel families were assessed using genotype data from the NEIGHBORHOOD consortium of 3853 cases and 33,480 controls. Rare (minor allele frequency

Abstract Necessity driven organisational change in the post-pandemic landscape has seen health care providers adopting innovations to manage and process health data. These include the use of ‘real-world’ datasets of routinely collected clinical information, enabling data-driven delivery. Rare disease risks being ‘left-behind’ unless our clinical and research communities engage with the challenges and opportunities afforded by the burgeoning field of health data informatics. We address the challenges to the meaningful use and reuse of rare disease data, and, through a series of recommendations around workforce education, harmonisation of taxonomy, and ensuring an inclusive health data environment, we highlight the role that those who manage rare disease must play in addressing them.

Abstract Glaucoma is a progressive optic neuropathy and a leading cause of irreversible blindness worldwide. Primary open-angle glaucoma is the most common form, and yet the etiology of this multifactorial disease is poorly understood. We aimed to identify plasma metabolites associated with the risk of developing POAG in a case-control study (599 cases and 599 matched controls) nested within the Nurses’ Health Studies, and Health Professionals’ Follow-Up Study. Plasma metabolites were measured with LC-MS/MS at the Broad Institute (Cambridge, MA, USA); 369 metabolites from 18 metabolite classes passed quality control analyses. For comparison, in a cross-sectional study in the UK Biobank, 168 metabolites were measured in plasma samples from 2,238 prevalent glaucoma cases and 44,723 controls using NMR spectroscopy (Nightingale, Finland; version 2020). Here we show higher levels of diglycerides and triglycerides are adversely associated with glaucoma in all four cohorts, suggesting that they play an important role in glaucoma pathogenesis.

A multi-ethnic meta-analysis of exome array data from over 27,000 participants identifies several rare variants that could contribute to risk of ocular refractive error.

The theoretical approach of Positive Youth Development Assets focuses on developmental assets that play a crucial role in the understanding of the whole person. According to the ecological approach of PYD, factors such as family support school climate, neighborhoods, communities, and the dispositions of adolescents to be more responsible, develop a sense of purpose, altruism, and commitment to education, are considered critical factors that help create a positive climate for adolescents to grow and flourish. This study aims to understand the role of the PYD framework in external and internal assets. This framework holistically saw adolescents, focusing on external and internal assets. External assets like Support, Empowerment, Boundaries, Expectations and Constructive Use of Time help adolescents create a climate that helps them feel supported and have a positive experience with people and other institutions. Internal assets are related to Commitment to learning, Positive values, Positive identity, and Social competencies. According to the current theoretical perspectives, the PYD model seems to be a valid method to explore factors that affect the positive development of adolescents and an excellent approach to building intervention programs for them.

Purpose The retina provides biomarkers of neuronal and vascular health that offer promising insights into cognitive ageing, mild cognitive impairment and dementia. This article described the rationale and methodology of eye and vision assessments with the aim of supporting the study of dementia in the UK Biobank Repeat Imaging study.Participants UK Biobank is a large-scale, multicentre, prospective cohort containing in-depth genetic, lifestyle, environmental and health information from half a million participants aged 40–69 enrolled in 2006–2010 across the UK. A subset (up to 60 000 participants) of the cohort will be invited to the UK Biobank Repeat Imaging Study to collect repeated brain, cardiac and abdominal MRI scans, whole-body dual-energy X-ray absorptiometry, carotid ultrasound, as well as retinal optical coherence tomography (OCT) and colour fundus photographs.Findings to date UK Biobank has helped make significant advances in understanding risk factors for many common diseases, including for dementia and cognitive decline. Ophthalmic genetic and epidemiology studies have also benefited from the unparalleled combination of very large numbers of participants, deep phenotyping and longitudinal follow-up of the cohort, with comprehensive health data linkage to disease outcomes. In addition, we have used UK Biobank data to describe the relationship between retinal structures, cognitive function and brain MRI-derived phenotypes.Future plans The collection of eye-related data (eg, OCT), as part of the UK Biobank Repeat Imaging study, will take place in 2022–2028. The depth and breadth and longitudinal nature of this dataset, coupled with its open-access policy, will create a major new resource for dementia diagnostic discovery and to better understand its association with comorbid diseases. In addition, the broad and diverse data available in this study will support research into ophthalmic diseases and various other health outcomes beyond dementia.

Summary: Background: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of the optic nerve that leads to irreversible visual impairment. Multiple epidemiological studies suggest an association between POAG and major neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease). However, the nature of the overlap between neurodegenerative disorders, brain morphology and glaucoma remains inconclusive. Method: In this study, we performed a comprehensive assessment of the genetic and causal relationship between POAG and neurodegenerative disorders, leveraging genome-wide association data from studies of magnetic resonance imaging of the brain, POAG, and four major neurodegenerative disorders. Findings: This study found a genetic overlap and causal relationship between POAG and its related phenotypes (i.e., intraocular pressure and optic nerve morphology traits) and brain morphology in 19 regions. We also identified 11 loci with a significant local genetic correlation and a high probability of sharing the same causal variant between neurodegenerative disorders and POAG or its related phenotypes. Of interest, a region on chromosome 17 corresponding to MAPT, a well-known risk locus for Alzheimer's and Parkinson's disease, was shared between POAG, optic nerve degeneration traits, and Alzheimer's and Parkinson's diseases. Despite these local genetic overlaps, we did not identify strong evidence of a causal association between these neurodegenerative disorders and glaucoma. Interpretation: Our findings indicate a distinctive and likely independent neurodegenerative process for POAG involving several brain regions although several POAG or optic nerve degeneration risk loci are shared with neurodegenerative disorders, consistent with a pleiotropic effect rather than a causal relationship between these traits. Funding: PG was supported by an NHMRC Investigator Grant (#1173390), SM by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144), DM by an NHMRC Fellowship, LP is funded by the NEI EY015473 and EY032559 grants, SS is supported by an NIH-Oxford Cambridge Fellowship and NIH T32 grant (GM136577), APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa.

Abstract To evaluate the influence AMD risk genomic variants have on macular thickness in the normal population. UK Biobank participants with no significant ocular history were included using the UK Biobank Resource (project 2112). Spectral-domain optical coherence tomography (SD-OCT) images were taken and segmented to define retinal layers. The influence of AMD risk single-nucleotide polymorphisms (SNP) on retinal layer thickness was analysed. AMD risk associated SNPs were strongly associated with outer-retinal layer thickness. The inner-segment outer segment (ISOS)-retinal pigment epithelium (RPE) thickness measurement, representing photoreceptor outer segments was most significantly associated with the cumulative polygenic risk score, composed of 33 AMD-associated variants, resulting in a decreased thickness (p = 1.37 × 10–67). Gene–gene interactions involving the NPLOC4-TSPAN10 SNP rs6565597 were associated with significant changes in outer retinal thickness. Thickness of outer retinal layers is highly associated with the presence of risk AMD SNPs. Specifically, the ISOS-RPE measurement. Changes to ISOS-RPE thickness are seen in clinically normal individuals with AMD risk SNPs suggesting structural changes occur at the macula prior to the onset of disease symptoms or overt clinical signs.

Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

Myopia most often develops during school age, with the highest incidence in countries with intensive education systems. Interactions between genetic variants and educational exposure are hypothesized to confer susceptibility to myopia, but few such interactions have been identified. Here, we aimed to identify genetic variants that interact with education level to confer susceptibility to myopia. Two groups of unrelated participants of European ancestry from UK Biobank were studied. A 'Stage-I' sample of 88,334 participants whose refractive error (avMSE) was measured by autorefraction and a 'Stage-II' sample of 252,838 participants who self-reported their age-of-onset of spectacle wear (AOSW) but who did not undergo autorefraction. Genetic variants were prioritized via a 2-step screening process in the Stage-I sample: Step 1 was a genome-wide association study for avMSE; Step 2 was a variance heterogeneity analysis for avMSE. Genotype-by-education interaction tests were performed in the Stage-II sample, with University education coded as a binary exposure. On average, participants were 58 years-old and left full-time education when they were 18 years-old; 35% reported University level education. The 2-step screening strategy in the Stage-I sample prioritized 25 genetic variants (GWAS P < 1e-04; variance heterogeneity P < 5e-05). In the Stage-II sample, 19 of the 25 (76%) genetic variants demonstrated evidence of variance heterogeneity, suggesting the majority were true positives. Five genetic variants located near GJD2, RBFOX1, LAMA2, KCNQ5 and LRRC4C had evidence of a genotype-by-education interaction in the Stage-II sample (P < 0.002) and consistent evidence of a genotype-by-education interaction in the Stage-I sample. For all 5 variants, University-level education was associated with an increased effect of the risk allele. In this cohort, additional years of education were associated with an enhanced effect of genetic variants that have roles including axon guidance and the development of neuronal synapses and neural circuits.

The genetic basis of cataract is not well understood. Here, the authors perform a genome-wide association multiethnic meta-analysis of cataract, finding 37 new loci and replicating known and new loci. They additionally perform sex-specific analyses, identifying new associations specific to women.

The epigenome has been shown to change with age, potentially impacting on ageing-related disease. Here the authors investigate the DNA methylation state of the genomic loci of human tRNA and observe enrichment for age-related DNA hypermethylation at tRNA loci.

Alison Hardcastle et al. report a genome-wide meta-analysis of keratoconus, a condition affecting the cornea that causes blurred vision and often leads to blindness. They identify 36 genomic regions associated with keratoconus, 31 of which are novel, and show that the genes in these regions implicate genetic pathways involved in collagen matrix integrity and cell differentiation.

Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.

Objective: Chronic obstructive pulmonary disease (COPD) is associated with atrial fibrillation (AF) and reduced forced expiratory volume (FEV1) is an independent predictor for new onset AF. The aims of this study were (1) to analyze the atrial electromechanical delay (AEMD) and P wave dispersion which are two predictors of AF development in patients with COPD and without any cardiovascular disease, and (2) to assess the relationship of those with pulmonary functions as quantified by FEV1 measurements. Methods: The study included 41 patients with COPD (33 male; mean age: 51 years) and 32 healthy controls. P wave dispersion was calculated as the difference between the maximum and minimum P wave duration in a 12-lead surface electrocardiography (ECG) recording. AEMD, defined as the time interval from the P wave onset on the ECG to the initiation of the late diastolic (Am) wave using a tissue Doppler examination, was measured from the lateral mitral annulus (LAEMD), septal annulus (SAEMD), and tricuspid lateral annulus (TAEMD). Results: P wave dispersion was significantly longer in the COPD group than those in the controls (76+-19 ms vs. 45+-10 ms; p

Objective: To investigate and compare the factors that motivated students to study dentistry in countries with similar background (Albania, Croatia and the Republic of Northern Macedonia) and to as-sess whether or not their motivation changed during time. Material and methods: In 2014/2015,cross-sectional studies were conducted in state funded dental schools in Tirana (Albania), Zagreb(Croatia) and Skopje (North Macedonia) to assess student views on their career motivation. All den-tal students from the first, third and final years of study were invited to participate. The participationwas voluntary and anonymous. A five-item questionnaire was translated into languages of the par-ticipating countries. Ethics approval was granted by the Ethics Committee of the University of SaintsCyril and Methodius, Skopje. The Chi square test was used to test if there were statistically significantdifferences in answers between students in 3 countries, furthermore between years of the study.Re-sults: The total number of respondents was 739 (319 in Tirana, 211 in Zagreb and 208 in Skopje) Thedifferences in the answers between the first-year students from all three countries were statistical-ly significant (χ2=82.65; p

PurposeGenetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort.MethodsGenetic association analyses of non-cyclopaedic autorefraction calculated as mean spherical equivalent (SPHE) used whole-exome sequence genotypic information from 50,893 unrelated participants in the UK Biobank of European ancestry. Gene-based analyses tested for association with SPHE using an optimised SNP-set kernel association test (SKAT-O) restricted to rare variants (minor allele frequency < 1%) within protein-coding regions of the genome. All models were adjusted for age, sex and common lead variants within the same locus reported by previous genome-wide association studies. Potentially causal markers driving association at significant loci were elucidated using sensitivity analyses by sequentially dropping the most associated variants from gene-based analyses.ResultsWe found strong statistical evidence for association of SPHE with the SIX6 (p-value = 2.15 x 10-10, or Bonferroni-Corrected p = 4.41x10-06) and the CRX gene (p-value = 6.65 x 10-08, or Bonferroni-Corrected p = 0.001). The SIX6 gene codes for a transcription factor believed to be critical to the eye, retina and optic disc development and morphology, while CRX regulates photoreceptor specification and expression of over 700 genes in the retina. These novel associations suggest an important role of genes involved in eye morphogenesis in refractive error.ConclusionThe results of our study support previous research highlighting the importance of rare variants to the genetic risk of refractive error. We explain some of the origins of the genetic signals seen in GWAS but also report for the first time a completely novel association with the CRX gene.

This study investigated temporal trends in the epidemiology of primary myopia and associations with key environmental risk factors in a UK population. Data were collected at recruitment (non-cycloplegic autorefraction, year of birth, sex, ethnicity, highest educational attainment, reason and age of first wearing glasses and history of eye disease) from 107,442 UK Biobank study participants aged 40 to 69 years, born between 1939 and 1970. Myopia was defined as mean spherical equivalent (MSE) ≤-1 dioptre (D). Temporal changes in myopia frequency by birth cohort (5-year bands using date of birth) and associations with environmental factors were analysed, distinguishing both type (childhood-onset,