A novel variant in GLIS3 is associated with osteoarthritis

Objectives Osteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date. Methods We carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR. Results We detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10−8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes. Conclusions We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits

Η πολιτική οικονομία της Ευρωπαϊκής Τραπεζικής Ένωσης

Η Οικονομική και Νομισματική Ένωση αποτέλεσε ένα ημιτελές έργο, οι νεολειτουργικές συνέπειες του οποίου επέβαλαν συνεχείς οικονομικές εξελίξεις. Η Ευρωπαϊκή Τραπεζική Ένωση αποτελεί μια από τις σημαντικότερες συμφωνίες της Ευρωπαϊκής ολοκλήρωσης, στοχεύοντας στη διάσπαση του φαύλου κύκλου μεταξύ κρατών και τραπεζών. Ο μηχανισμός εποπτείας, ο μηχανισμός εξυγίανσης, καθώς και το σύστημα εγγύησης καταθέσεων συντείνουν προς αυτή την κατεύθυνση, αν και τα αποτελέσματα δεν είναι ακόμη ορατά σε όλα τα κράτη – μέλη της Ε.Ε. Στην παρακάτω πτυχιακή εργασία, θα εξεταστεί τόσο το ισχύον πλαίσιο, όσο και ο προβληματισμός για την αποτελεσματικότητα και τις αδυναμίες του.The Economic and Monetary Union was an unfinished project, with neofunctional consequences that imposed further economic developments. The European Banking Union constitutes one of the most important agreements of European integration, aiming at disrupting the vicious circle between states and banks. The Supervisory mechanism, the resolution mechanism and deposit guarantee scheme contribute to this direction, although results are not yet visible to all member – states of EU. In the following dissertation, both the current framework and the questioning for its actual efficacy and its weaknesses will be examined

Genome-wide association study of knee pain identifies associations with GDF5 and COL27A1 in UK Biobank

Knee pain is one of the most common musculoskeletal complaints that brings people to medical attention. Approximately 50% of individuals over the age of 50 report an experience of knee pain within the past 12 months. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and seek supporting evidence in cohorts from 23andMe, the Osteoarthritis Initiative, and the Johnston County Osteoarthritis Project. We identified two loci that reached genome-wide significance in the UK Biobank: rs143384, located in GDF5 (P = 1.32 × 10−12), a gene previously implicated in osteoarthritis; and rs2808772, located near COL27A1 (P = 1.49 × 10−8). These findings were supported in cohorts with self-reported osteoarthritis/radiographic knee osteoarthritis without pain information. In this report on genome-wide association of knee pain, we identified two loci in or near GDF5 and COL27A1 that are associated with knee pain

Pathways to understanding the genomic aetiology of osteoarthritis

Osteoarthritis is a common, complex disease with no curative therapy. In this review, we summarize current knowledge on disease aetiopathogenesis and outline genetics and genomics approaches that are helping catalyse a much-needed improved understanding of the biological underpinning of disease development and progression

Combination therapy as a potential risk factor for the development of type 2 diabetes in patients with schizophrenia: the GOMAP study.

BACKGROUND: Schizophrenia (SCZ) is associated with increased risk of type 2 diabetes (T2D). The potential diabetogenic effect of concomitant application of psychotropic treatment classes in patients with SCZ has not yet been evaluated. The overarching goal of the Genetic Overlap between Metabolic and Psychiatric disease (GOMAP) study is to assess the effect of pharmacological, anthropometric, lifestyle and clinical measurements, helping elucidate the mechanisms underlying the aetiology of T2D. METHODS: The GOMAP case-control study (Genetic Overlap between Metabolic and Psychiatric disease) includes hospitalized patients with SCZ, some of whom have T2D. We enrolled 1653 patients with SCZ; 611 with T2D and 1042 patients without T2D. This is the first study of SCZ and T2D comorbidity at this scale in the Greek population. We retrieved detailed information on first- and second-generation antipsychotics (FGA, SGA), antidepressants and mood stabilizers, applied as monotherapy, 2-drug combination, or as 3- or more drug combination. We assessed the effects of psychotropic medication, body mass index, duration of schizophrenia, number of hospitalizations and physical activity on risk of T2D. Using logistic regression, we calculated crude and adjusted odds ratios (OR) to identify associations between demographic factors and the psychiatric medications. RESULTS: Patients with SCZ on a combination of at least three different classes of psychiatric drugs had a higher risk of T2D [OR 1.81 (95% CI 1.22-2.69); p = 0.003] compared to FGA alone therapy, after adjustment for age, BMI, sex, duration of SCZ and number of hospitalizations. We did not find evidence for an association of SGA use or the combination of drugs belonging to two different classes of psychiatric medications with increased risk of T2D [1.27 (0.84-1.93), p = 0.259 and 0.98 (0.71-1.35), p = 0.885, respectively] compared to FGA use. CONCLUSIONS: We find an increased risk of T2D in patients with SCZ who take a combination of at least three different psychotropic medication classes compared to patients whose medication consists only of one or two classes of drugs

The Use of Technology in the Subcategorisation of Osteoarthritis: a Delphi Study Approach

Objective This UK-wide OATech Network + consensus study utilised a Delphi approach to discern levels of awareness across an expert panel regarding the role of existing and novel technologies in osteoarthritis research. To direct future cross-disciplinary research it aimed to identify which could be adopted to subcategorise patients with osteoarthritis (OA). Design An online questionnaire was formulated based on technologies which might aid OA research and subcategorisation. During a two-day face-to-face meeting concordance of expert opinion was established with surveys (23 questions) before, during and at the end of the meeting (Rounds 1, 2 and 3, respectively). Experts spoke on current evidence for imaging, genomics, epigenomics, proteomics, metabolomics, biomarkers, activity monitoring, clinical engineering and machine learning relating to subcategorisation. For each round of voting, ≥80% votes led to consensus and ≤20% to exclusion of a statement. Results Panel members were unanimous that a combination of novel technological advances have potential to improve OA diagnostics and treatment through subcategorisation, agreeing in Rounds 1 and 2 that epigenetics, genetics, MRI, proteomics, wet biomarkers and machine learning could aid subcategorisation. Expert presentations changed participants’ opinions on the value of metabolomics, activity monitoring and clinical engineering, all reaching consensus in Round 2. X-rays lost consensus between Rounds 1 and 2; clinical X-rays reached consensus in Round 3. Conclusion Consensus identified that 9 of the 11 technologies should be targeted towards OA subcategorisation to address existing OA research technology and knowledge gaps. These novel, rapidly evolving technologies are recommended as a focus for emergent, cross-disciplinary osteoarthritis research programmes

Genome-wide association study of developmental dysplasia of the hip identifies an association with GDF5

Developmental dysplasia of the hip (DDH) is the most common skeletal developmental disease. However, its genetic architecture is poorly understood. We conduct the largest DDH genome-wide association study to date and replicate our findings in independent cohorts. We find the heritable component of DDH attributable to common genetic variants to be 55% and distributed equally across the autosomal and X-chromosomes. We identify replicating evidence for association between GDF5 promoter variation and DDH (rs143384, effect allele A, odds ratio 1.44, 95% confidence interval 1.34–1.56, P = 3.55 × 10−22). Gene-based analysis implicates GDF5 (P = 9.24 × 10−12), UQCC1 (P = 1.86 × 10−10), MMP24 (P = 3.18 × 10−9), RETSAT (P = 3.70 × 10−8) and PDRG1 (P = 1.06 × 10−7) in DDH susceptibility. We find shared genetic architecture between DDH and hip osteoarthritis, but no predictive power of osteoarthritis polygenic risk score on DDH status, underscoring the complex nature of the two traits. We report a scalable, time-efficient recruitment strategy and establish for the first time to our knowledge a robust DDH genetic association locus at GDF5

Evaluating the glucose raising effect of established loci via a genetic risk score.

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with glucose levels. We tested the hypothesis here whether the cumulative effect of glucose raising SNPs, assessed via a score, is associated with glucose levels. A total of 1,434 participants of Greek descent from the THISEAS study and 1,160 participants form the GOMAP study were included in this analysis. We developed a genetic risk score (GRS), based on the known glucose-raising loci, in order to investigate the cumulative effect of known glucose loci on glucose levels. In the THISEAS study, the GRS score was significantly associated with increased glucose levels (mmol/L) (β ± SE: 0.024 ± 0.004, P = 8.27e-07). The effect of the genetic risk score was also significant in the GOMAP study (β ± SE: 0.011 ± 0.005, P = 0.031). In the meta-analysis of the two studies both scores were significantly associated with higher glucose levels GRS: β ± SE: 0.019 ± 0.003, P = 1.41e-09. Also, variants at the SLC30A8, PROX1, MTNR1B, ADRA2A, G6PC2, LPIN3 loci indicated nominal evidence for association with glucose levels (p < 0.05). We replicate associations of the established glucose raising variants in the Greek population and confirm directional consistency of effects (binomial sign test p = 6.96e-05). We also demonstrate that the cumulative effect of the established glucose loci yielded a significant association with increasing glucose levels

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation