The predictive power of polygenic scores (PGSs) for lithium treatment response in bipolar disorder (BD) remains limited. To enhance prediction of lithium responsiveness by developing a multi-trait PGS (mt-PGS) combining genetic information from multiple phenotypes implicated in lithium response and/or BD aetiology. We analysed data collected from BD patients who had received lithium treatment for at least six months and participated in the International Consortium on Lithium Genetics (ConLi+Gen, N=2,367) study. The ALDA scale was used to assess lithium responsiveness, and treatment outcome was defined as continuous ALDA score (0-10) and categorical outcome (favourable ≥7 vs unfavourable response). PGSs were calculated for 59 phenotypes grouped into five clinical-biological clusters: clinical lithium exemplar (#22 phenotypes), cardiometabolic (#17), autoimmune/inflammatory (#5), neurocognitive (#8) and renal function (#7). We applied cross-validated machine learning regression approaches in both outcomes within each cluster, and the selected features from each cluster were subsequently combined to construct the final mt-PGS models. Model performance was assessed using explained variance (R2) for the continuous outcome, and McFadden's pseudo-R2 as well as standard classification model parameters for the categorical outcomes. The mt-PGS explained 5.07% (continuous outcome) to 9.02% (categorical outcome) of the interindividual variability in lithium responsiveness. Classification accuracy (AUC) for the categorical outcome was 68.13% (95% CI: 64.86, 71.77). Of the five clusters, the PGSs for clinical lithium exemplar phenotypes were most strongly associated with lithium responsiveness, accounting for 2.97%-6.20% of its variability. By integrating polygenic scores for multiple relevant phenotypes, predictive accuracy for lithium response improved up to nine-fold compared to single-trait methods. Future research incorporating larger, more diverse populations and combining genetic scores with clinical data holds promise for further enhancing prediction and advancing clinical implementation.
Epstein-Barr virus (EBV) infects approximately 90-95% of the global population1,2 and persists in B cells as a lifelong infection3. Previous EBV infection is associated with autoimmune and neoplastic disease4. Still, the biological basis of host control during EBV persistence remains unclear. Here we report the identification of non-genetic and genetic factors that are associated with EBV control during persistent infection. Using blood-based genome sequence data from 486,315 UK Biobank and 336,123 All of Us participants, we identified short-read pairs mapping to the EBV genome in 16.2% and 21.8% of individuals, respectively. EBV read detection (EBVread+) reflects increased viral load in blood cells, as shown by orthogonal measurements, and was associated with HIV infection, immunosuppressive drug intake and current smoking. Genome-wide analyses of EBVread+ identified strong associations at the major histocompatibility complex (MHC), including 54 independent human leukocyte antigen (HLA) alleles of MHC classes I and II, and at 27 genomic regions outside MHC. Epistasis with distinct HLA alleles of MHC class I was observed at the ERAP2 locus. Analysis of individuals with EBV-associated diseases4 revealed a higher polygenic burden of EBVread+ for HLA alleles at MHC class I in multiple sclerosis (driven by HLA-A*02:01) and at MHC class II in rheumatoid arthritis. Phenome-wide analyses identified a polygenic overlap of EBVread+ with inflammatory bowel disease, hypothyroidism and type 1 diabetes. Our study establishes by-products of human genome sequencing as a surrogate marker of EBV viral load. This will facilitate investigation and treatment for EBV and other persistent viral infections.
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Although low-grade inflammatory processes have traditionally been studied in affective disorders, they are increasingly recognized as relevant across diagnostic categories. Genetic predisposition and environmental exposures such as childhood trauma (CT) may influence inflammation and shape vulnerability to psychopathology. Understanding how genetic predisposition for inflammation relates to specific symptom dimensions may clarify biological mechanisms underlying psychopathology. In N = 1790 individuals from the Marburg-Münster Affective Disorders Cohort Study (MACS), including patients with affective, anxiety, and psychotic disorders, as well as healthy controls, five transdiagnostic psychopathological syndrome factors were derived using factor analysis of clinical ratings. Polygenic scores (PGS) for circulating tumor necrosis factor TNF-α, interleukin IL-6, IL-10, and CRP were computed to indicate genetic predisposition to low-grade inflammation. Using network analyses, associations between inflammatory PGS and psychopathological syndrome factors were estimated while adjusting for age, sex, and BMI and including CT as a potential moderator. Six direct PGS-syndrome associations emerged, all with small but stable effect sizes. IL-6 PGS had the broadest connectivity, showing negative associations with increased appetite, paranoid-hallucinatory syndrome, and depression, as well as a positive association with negative syndrome. It also had the highest bridging centrality. IL-10 PGS was connected to negative and paranoid hallucinatory syndromes. These associations were largely independent of diagnosis and CT exposure. Integrating inflammatory genetic predisposition into networks of transdiagnostic symptom dimensions reveals small but consistent links between immune-related genetic risk and psychopathology, highlighting shared and distinct immunological pathways across psychiatric disorders.
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Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD. To identify genetic risk loci and cardiovascular risk factors with AS-specific associations. This was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023. Genetic variants. Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts. A total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10-3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10-5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development. This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.
The majority of patients with chronic tic disorders suffer from psychiatric comorbidities, most frequently attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), depression, and anxiety. While characteristics of these psychiatric disorders are widely known, other comorbidities including self-injurious behaviors (SIB) and body focused repetitive behaviors (BFRB) are still under-investigated. Currently, there is a controversial discussion whether BFRB and SIB belong to the same spectrum because of clinical similarities or they represent distinct entities. In this study, we investigated the clinical profile of BFRB in a large sample of adult patients (N = 123) with chronic tic disorders. Current urge and/or behavior to perform BFRB was reported by 59 participants (48%). BFRB were overall more frequent in females, individuals with comorbid OCD, and more severe tics. Both urges and behaviors to perform BFRB had a negative impact on quality of life. When comparing patients with comorbid SIB and those with comorbid BFRB, SIB was found in younger patients with more severe tics and comorbid ADHD. From our data it is suggested that SIB and BFRB belong to the same spectrum with SIB indicating the more severe clinical manifestation.
Tourette Syndrome (TS) is a childhood onset chronic disorder in which motor and vocal tics co-occur. Cannabinoids are a potential therapeutic option for otherwise treatment resistant patients. However, there is an ongoing debate regarding potential side effects. This is particularly important in relation to activities being necessary for daily life such as driving a car. We present the case of a 28-year-old male with TS and comorbid attention-deficit/hyperactivity disorder (ADHD) who was medicated by his treating physician with an extremely high dose of inhaled medicinal cannabis (MC) of up to 10 g/d. We were interested in the effects of MC on patient's fitness to drive as well as corresponding serum levels of tetrahydrocannabinol (THC) and its metabolites. Therefore, clinical assessments and computer-based tests (Vienna Test System) were performed at different time points at two consecutive days before and after intake of MC at a dose that was determined by the patient according to clinical need. On day 1, he inhaled a total dose of 3.3 g and 4.1 g MC, respectively, before driving tests were performed. Until the end of the day, he used a total dose of 8.8 g. On day 2, he took no MC before all tests were completed. Remarkably, according to the German Federal Highway Research Institute guidelines, the patient was considered fit to drive in all domains assessed at all time points at day 1 and 2. Higher doses of MC - and corresponding very high THC serum levels - resulted in best results with respect to patient's driving ability. THC serum levels ranged from 19 ng/ml (at day 2 without MC intake at this day) to 364 ng/ml (at day 1 after intake of a total of 3.3 g MC at the same day). No clinically relevant side effects occurred. This case study demonstrates that patients with TS plus comorbid ADHD may be fit to drive even after intake of high doses of MC. In any case, however, every driver, who uses MC, is obliged to check fitness to drive before driving a vehicle.
Tourette syndrome and other tic disorders are prevalent neurodevelopmental disorders typically treated with behavioral techniques or pharmacological interventions, primarily antipsychotics. However, many patients do not achieve sufficient response to conventional treatments, underscoring the need for further research in this area. To provide a comprehensive overview of ongoing research activities, we systematically searched the clinical registries of the World Health Organization (WHO) and of the United States National Institutes of Health (NIH) for currently planned or ongoing registered clinical studies. Our search identified 21 registered studies, of which seven focus specifically on pharmacological interventions. Potential candidates include the dopamine D1 antagonist ecopipam, the phosphodiesterase inhibitor gemlapodect, and cannabis-based therapies. Additionally, several studies are exploring behavioral interventions including Comprehensive Behavioral Interventions for Tics (CBIT) and mindfulness training, neurostimulation including MRI-navigated transcranial stimulation, theta burst stimulation, and deep brain stimulation, traditional Chinese medicine, and other approaches such as microbiota transplantation. Despite the range of research activities underway, the overall landscape remains limited. In this report we will discuss the findings, current developments, and relevant aspects concerning future research including clinical, scientific, and patient perspectives.
We conducted the largest genome-wide meta-analysis of borderline personality disorder (BPD) to date, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci, and nine risk genes in the gene-based analysis. We observed a single-nucleotide polymorphism (SNP) heritability of 17.3% and derived polygenic scores (PGS) predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of posttraumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide association analyses using BPD-PGS confirmed these associations and additionally revealed associations with general medical conditions including obstructive pulmonary disease and diabetes. The present analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.
Placebo, nocebo, and lessebo effects are very frequent in patients with both neurological and psychiatric disorders. Interestingly, the neural mechanisms underlying placebo effects have been found to be the same as or similar to mechanisms targeted by active pharmaceutical interventions for many of these disorders. In the case of functional neurological disorders (FNDs), there are shared neural substrates between the central nervous system "placebo network" and the dysfunctional networks implicated in the pathophysiology. These networks are primarily involved in emotion regulation, stress responses, and the sense of self-agency. Therefore, placebo effects have also been discussed as therapeutic interventions in FNDs. Such an approach, however, has a variety of ethical implications evolving around informed consent, autonomy, nonmaleficence, beneficence, and justice. In this paper, we discuss the use of placebo, nocebo, and lessebo in FNDs as well as related ethical issues. Overall, the use of placebo in FNDs is currently still considered controversial both for diagnostic as well as therapeutic purposes. Although it is a safe and almost unique intervention, its use violates the core principles of medical ethics and doctor-patient interactions involving autonomy or openness in the therapeutic relationship.
The power of genome-wide association studies (GWAS) to identify common disease variants depends primarily on the number of included samples. The availability of formalin-fixed paraffin-embedded (FFPE) samples in pathology institutes provides a valuable resource for GWAS, but the use of this material poses significant challenges. To explore the suitability of utilizing FFPE tissue for GWAS, we analysed the genotyping concordance between corresponding FFPE and blood samples. We evaluated both microarray technology and low-coverage whole-genome sequencing (lcWGS) to determine whether there were differences between genotyping methods. In our concordance study, FFPE tissue showed high recall and precision values across both genotyping methods when compared to matched blood samples for single nucleotide polymorphisms. This demonstrates that FFPE samples are suitable for GWAS and that both methods are viable options for genotyping. However, microarray technology outperformed lcWGS, as evidenced by significantly higher recall (p = 0.005) and precision (p = 0.003) values. This, together with the lower cost of genotyping and computational efficiency, makes microarray technology currently the superior method for GWAS using FFPE tissue. Nevertheless, lcWGS has shown reliable results and holds the potential to provide more comprehensive and unbiased genetic variant analysis across diverse populations in the future. Our results show that the large number of FFPE samples stored in pathology institutes can significantly increase the power of future GWAS. The online version contains supplementary material available at 10.1186/s13104-025-07306-z.
Tic disorders are neurodevelopmental disorders characterized by involuntary motor and/or vocal expressions (tics). According to ICD-10 and ICD-11 classifications they are differentiated into transient (≤ 12 months) and chronic (> 12 months) tic disorders; the diagnosis of Tourette syndrome requires the presence of multiple motor tics and at least one vocal tic persisting for more than 1 year. Typical features of tics include onset in childhood, a premonitory urge, at least partial suppressibility and a rostrocaudal distribution. Differential diagnoses include other hyperkinetic neurological disorders as well as obsessive-compulsive symptoms, stereotypes and functional tic-like behaviors, the latter often presenting with a late, abrupt onset and predominantly complex expressions. Behavioral therapy is considered the first-line treatment for clinically relevant tics. Pharmacological treatment includes off-label use of dopamine antagonists, such as aripiprazole. Comorbidities are common and require targeted comanagement. Tic-Störungen sind Entwicklungsstörungen, die durch unwillkürliche motorische und/oder vokale Entäußerungen (Tics) gekennzeichnet sind. In der International Statistical Classification of Diseases and Related Health Problems (ICD) 10 und 11 wird zwischen transienten (≤ 12 Monate) und chronischen Tic-Störungen (> 12 Monate) unterschieden; liegen multiple motorische und mindestens ein vokaler Tic chronisch vor, ist das Tourette-Syndrom zu diagnostizieren. Charakteristisch für Tics sind ein Beginn im Kindesalter, ein vorangehendes Dranggefühl, eine zumindest teilweise Unterdrückbarkeit sowie eine rostrokaudale Verteilung. Differenzialdiagnostisch sind neben anderen hyperkinetischen neurologischen Erkrankungen insbesondere Zwangshandlungen, Stereotypien und funktionelle Tic-ähnliche Störungen abzugrenzen. Letztere zeichnen sich u. a. durch einen meist späten, oft abrupten Beginn und überwiegend komplexe Entäußerungen aus. Die Verhaltenstherapie stellt die Behandlung der ersten Wahl bei therapiebedürftigen Tics dar. Medikamentös kann eine Off-label-Behandlung mit Dopaminantagonisten wie z. B. Aripiprazol erfolgen. Komorbiditäten sind häufig und erfordern eine gezielte Mitbehandlung.
Cannabis-based medicine (CBM) is recommended for the treatment of tics in otherwise treatment-resistant adult patients with Tourette syndrome (TS). However, evidence in children with TS is very limited. Long-term effects of CBM in this population are unknown. We present two cases of long-term follow-up over six and five years, respectively, in male adolescents with TS who were administered CBM starting at the age of eight and 12 years, respectively. In one patient CBM treatment was initiated with pure tetrahydrocannabinol (THC) and was later changed to current treatment with an oral THC-dominant cannabis extract (THC:cannabidiol (CBD)=25:<0.5) with a daily dose of 0.5-0.6 mL (corresponding to 12.5-15 mg THC/day). The other patient was from the beginning up to now medicated by his parents, who are physicians, with vaporized THC-dominant (24%) medicinal cannabis flowers with a dose of 0.2 g between once to thrice per day (corresponding to 48-144 mg THC/day). While in one patient, there was a moderate dose increase over the years, in the other patient dosages were adjusted individually depending on tic severity. In both patients, CBM treatment resulted in continued benefit with significant improvement of tics and psychiatric comorbidities without severe adverse effects. Academic performance of both adolescents was excellent. Neurocognitive assessments demonstrated average results in the domain of working memory and average to above average results in the domain of processing speed. We present two cases of minors with TS who started CBM treatment at the age of eight and 12 years, respectively, and continued treatment for five to six years resulting in clinically relevant symptom improvement without any severe adverse effects or negative impact on cognitive and academic performance.
Angioedema (AE) rarely occurs as a potentially life-threatening adverse drug reaction (ADR) to angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). The aim of the present study was to investigate non-genetic association factors with ACEi-/ARB-induced angioedema in the European ADR database EudraVigilance and the database of the vARIANCE study. The cohort of the vARIANCE study comprised 114 patients who suffered from ACEi- or ARB-induced angioedema. In addition, 171 angioedema reports and 4650 reports on other ADRs of ACEi/ARB were identified in the ADR database EudraVigilance with the latter serving as a reference group. Odds ratios were calculated and a logistic regression analysis was performed using angioedema versus reference reports. Increased age, smoking, allergies and a history of previous angioedema were identified as associated factors for ACEi-/ARB-induced angioedema. In most patients, the swelling affected the face, lips and tongue. In the vARIANCE study, about 70% of angioedema occurred after 1 year of treatment. For one in two patients in the vARIANCE study (84.2% with ACEi treatment) and one in three patients from the EudraVigilance reports (59.6% with ARB treatment), the angioedema resulted in hospitalization. We found small to moderate associations with certain individual patient-related factors in this pharmaco-epidemiological study. As a future perspective, combining non-genetic association factors with corresponding genetic data might provide an option to compose stronger and individual risk scores.
Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but the benefits and risks in survivors of intracerebral haemorrhage are uncertain. We aimed to determine whether DOACs reduce the risk of ischaemic stroke without substantially increasing the risk of recurrent intracerebral haemorrhage. PRESTIGE-AF is a multicentre, open-label, randomised, phase 3 trial conducted at 75 hospitals in six European countries. Eligible patients were aged 18 years or older with spontaneous intracerebral haemorrhage, atrial fibrillation, an indication for anticoagulation, and a score of 4 or less on the modified Rankin Scale. Patients were randomly assigned (1:1) to a DOAC or no anticoagulation, stratified by intracerebral haemorrhage location and sex. Only the events adjudication committee was masked to treatment allocation. The coprimary endpoints were first ischaemic stroke and first recurrent intracerebral haemorrhage. Hierarchical testing for superiority and non-inferiority, respectively, was performed in the intention-to-treat population. The margin to establish non-inferiority regarding intracerebral haemorrhage was less than 1·735. The safety analysis was done in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03996772, and is complete. Between May 31, 2019, and Nov 30, 2023, 319 participants were enrolled and 158 were randomly assigned to the DOAC group and 161 to the no anticoagulant group. Patients' median age was 79 years (IQR 73-83). 113 (35%) of 319 patients were female and 206 (65%) were male. Median follow-up was 1·4 years (IQR 0·7-2·3). First ischaemic stroke occurred less frequently in the DOAC group than in the no anticoagulant group (hazard ratio [HR] 0·05 [95% CI 0·01-0·36]; log-rank p<0·0001). The rate of all ischaemic stroke events was 0·83 (95% CI 0·14-2·57) per 100 patient-years in the DOAC group versus 8·60 (5·43-12·80) per 100 patient-years in the no anticoagulant group. For first recurrent intracerebral haemorrhage, the DOAC group did not meet the prespecified HR for the non-inferiority margin of less than 1·735 (HR 10·89 [90% CI 1·95-60·72]; p=0·96). The event rate of all intracerebral haemorrhage was 5·00 (95% CI 2·68-8·39) per 100 patient-years in the DOAC group versus 0·82 (0·14-2·53) per 100 patient years in the no anticoagulant group. Serious adverse events occurred in 70 (44%) of 158 patients in the DOAC group and 89 (55%) of 161 patients in the no anticoagulant group. 16 (10%) patients in the DOAC group and 21 (13%) patients in the no anticoagulant group died. DOACs effectively prevent ischaemic strokes in survivors of intracerebral haemorrhage with atrial fibrillation but a part of this benefit is offset by a substantially increased risk of recurrent intracerebral haemorrhage. To optimise stroke prevention in these vulnerable patients, further evidence from ongoing trials and a meta-analysis of randomised data is needed, as well as the evaluation of safer medical or mechanical alternatives for selected patients. European Commission.
The Hippocratic Oath is one of the most known medical texts. Despite its importance, it was rarely used in art and music. There exist only two complex musical settings of the Hippocratic Oath: "SERMENT-ΟΡΚΟΣ pour chœur mixte" ("Oath for mixed chorus") by Iannis Xenakis (1922-2001) and "Der Eid des Hippokrates für Klavier zu 3 Händen" ("The Hippocratic Oath for piano three hands") by Mauricio Kagel (1931-2008). Both being among the most important composers of the 20th century: Xenakis attempted to apply stochastic processes to his compositional techniques and Kagel is considered a pioneer of instrumental theatre. Both musical settings of the Hippocratic Oath were commissioned by medical institutions: Xenakis composed the work "Serment" in 1981 as a commission for the 15th World Congress of the "International Society of Cardiovascular Surgery" in Athens. "Der Eid des Hippokrates" was composed by Kagel in 1984 on behalf of the German medical journal "Deutsches Ärzteblatt". Both works are therefore intended for medical practitioners and both are influenced by the pathography of the two composers. This article will present results of the analysis and interpretation from a medical-historical perspective.