Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Diagnosis, risk assessment, and treatment decisions for tooth wear in daily practice: a case presentation survey among Belgian dentists.

This survey assessed the use of current concepts for tooth wear diagnosis, risk assessment, and treatment decisions in daily practice, and identified factors of significance for treatment decisions. A total of 104 dentists were presented with 10 cases representing varying degrees of tooth wear. The dentists were asked to answer six questions pertaining to the diagnosis, risk assessment, and treatment of each case. A benchmark was established by three experts and the agreement between dentists and the benchmark was calculated. At dentition level, the agreement was moderate for diagnosis (κ = 0.55) and risk assessment (κ = 0.54). At tooth/surface level, the agreement for clinical and radiographic severity of wear was moderate (κ = 0.57) and substantial (κ = 0.65), respectively. The agreement for treatment decision was fair (κ = 0.35). Multivariate logistic regression analysis showed that treatment decisions for operative treatment were associated with moderate to high case risk (OR = 10.1; 95% CI: 5.4-18.9). Belgian dentists performed reasonably well in applying current concepts and strategies for tooth wear diagnosis and risk assessments at dentition level, as well as for assessment of wear severity at tooth/surface level. Improvement is warranted concerning treatment decisions. This survey could be a useful tool for disseminating and improving current knowledge of tooth wear, and for training dentists in daily practice

Teaching Tooth Wear Diagnosis, Risk Assessment, and Treatment Decisions Applying Inverted Classroom Combined with Case Presentation Model.

This study explored the application of a model for teaching tooth wear diagnosis, risk assessment, and treatment decisions to undergraduates at the UCLouvain, Belgium, based on an inverted classroom combined with case presentations. The aim was to explain its implementation and assess improvement in learning, engagement, and satisfaction. The hypothesis tested was that this model would enhance students' performance. This controlled clinical trial included 29 dental students in the test group and 30 in the control group. All students received instructions and pre-class material for reading via e-mail 2 weeks prior to class time (T0). The test group included students attending the class time (attendance was not obligatory). The control group consisted of students only attending the preclinical training (attendance was obligatory). Both groups assessed three case presentations with no, moderate, and severe erosive tooth wear. The test group assessed the cases at the beginning of the class time (T1). One week later, at the beginning of the preclinical training, the students of the control group assessed the case presentations (T2). In parallel, to measure the contribution of the class time to students' performance, the test group reassessed the cases (T2). This was followed by discussion of each case in which the lecturer presented the benchmark assessments. Students' perception of their learning experience was recorded. The generalized linear mixed regression model showed that for the overall assessments of cases, students in the control group were significantly less likely to agree with the benchmark than students in the test group (OR = 0.62; p = 0.006). Students' satisfaction was higher in the test group than in the control group but only significantly regarding the quality of the cases presentations (Fisher test p < 0.01). The class time contributed significantly to students' improvement in learning in the test group (liner mixed model; p < 0.01). In conclusion, the model applied improved significantly in performance, learning, and to some extent satisfaction. However, the motivation strategy applied resulted in only half of the students adhering/engaging to the complete interactive model of teaching. Further motivation strategies should be implemented to make the complete model more widely accepted by students

Tooth wear and oral-health-related quality of life in dentate adults.

OBJECTIVES: This study estimated the extent to which tooth wear, adjusted for (oral) health risk indicators, impacts adversely on the Oral-Health-Related Quality of Life (OHRQoL) of dentate adults. METHODS: A cross-sectional study was conducted and had a convenience sample of 570 adults ≥18 years old with at least one bilateral molar occlusal contact. Participants answered a self-applied questionnaire (ICC=0.71) consisting of four domains: socio-demographics, oral care attendance, (oral) health conditions and lifestyle, complaints and oral-health-related quality of life (OHIP-14). Tooth wear was clinically assessed using the Basic Erosive Wear Examination index by two examiners, whose inter-examiner reliability were k=0.76-0.80. RESULTS: The outcome was a high score on the OHRQoL (median split ≥ 7). The prevalence of tooth wear was 75.0%. Only 30.2% of adults reported impacts on at least 1 performance parameter affected 'fairly often' or 'very often'. The hierarchical logistic regression showed that participants 35-54 years old (OR=2.1), who were ever prevented from regular oral health care due to costs of care (OR=3.6), who ingested acidic beverages ≥ daily (OR=1.7), who had tooth sensitivity (OR= 2.9) and those having the impression that their teeth have changed appearance (OR= 5.9) were significantly more likely to report lower OHRQoL than their counterparts. The severity of tooth wear was not significant when considering moderate and severe cases together. CONCLUSIONS: Although the prevalence of tooth wear was high, its severity and impact on OHRQoL were limited. However, distal and proximal indicators for tooth wear were mediators for impaired OHRQoL and treatment needs. CLINICAL SIGNIFICANCE: Prevalence and severity of tooth wear had limited impact on OHRQoL in adults. Distal and proximal indicators for tooth wear were mediators for impaired OHRQoL. The understanding of these relationships offers an opportunity to assess in depth the treatment needs and quality of life of patients affected by tooth wear

Diagnosis, Risk Assessment and Treatment Decisions for Tooth Wear: A Case-Based Survey Among Belgian Dentists

This study validated a case-based survey method and analyzed the extent to which Belgian dentists apply current concepts and strategies for tooth wear diagnosis, risk assessment and treatment decisions. A case-based, pre-coded questionnaire consisting of 10 clinical cases/patients with 20 teeth was developed. The cases were set up in a PowerPoint presentation illustrating patients with different types of tooth wear, levels of severity and risk. Dentists (n = 104), recruited at continued education courses, were from 8% of Belgian municipalities [...

Non-Biological and Biological Risk Indicators for Tooth Wear Outcomes in Adults.

This study was undertaken to estimate the prevalence and severity of tooth wear (TW), as well as to assess non-biological and biological risk indicators for TW outcomes in adults. A cross-sectional study, adhering to the reporting STROBE guidelines, was conducted and had a convenience sample of adults ≥18 years of age who had at least one bilateral posterior molar contact. A total of 570 participants, seeking consultation at the University Hospital in Brussels, Belgium, were allocated to three age groups: 18-34 years (n = 232), 35-54 years (n = 256), and ≥55 years old (n = 79). Participants answered a self-applied questionnaire regarding sociodemographics, oral hygiene, and lifestyle behavior. The questionnaire was tested-retested (intraclass correlation coefficient = 0.71). Inter-examiner reliability for clinical examinations was k = 0.76-0.80. The prevalence of TW was 75% (95% CI: 71.7-78.9). Out of these patients, 42% (95% CI: 38.0-46.3) had as the primary etiological factor the process of dental erosion, while 22% (95% CI: 18.9-25.9) and 11% (95% CI: 8.6-13.9) had the processes of dental attrition and dental abrasion, respectively. The severity of TW according to BEWE highest score was mild in 31%, moderate in 28%, and severe in 17% of participants. The hierarchical logistic regression model for the association between risk indicators and TW irrespective of the etiology was significant for age (>35-54 years: OR = 2.35 and ≥55 years: OR = 3.89; p male: OR = 2.03; p sensitive teeth: OR = 2.34; p = 0.005), occlusal splint (>yes: OR = 1.62; p = 0.03), and acidic beverages (≥once per day: OR = 1.62; p = 0.044). Consumption of acidic beverages was not associated with TW having as the primary etiological factor the process of dental attrition or dental abrasion, while it was significantly associated with the process of dental erosion (>once per week: OR = 1.69; p = 0.043 and ≥once per day: OR = 1.73; p = 0.016). Medical conditions were equally associated with the latter (OR = 3.11; p < 0.001). These findings could contribute to improving the effectiveness and sustainability of awareness in contemporary adult populations. In conclusion, the prevalence and severity of TW in adults were substantial. Medical conditions and consumption of acidic beverages were risk indicators for TW having as the primary etiological factor the process of dental erosion, although associations were moderate and weak, respectively

Helicase-inactivating BRIP1 mutation yields Fanconi anemia with microcephaly and other congenital abnormalities

Fanconi anemia is a genetically and phenotypically heterogeneous disorder characterized by congenital anomalies, bone marrow failure, cancer, and sensitivity of chromosomes to DNA cross-linking agents. One of the 22 genes responsible for Fanconi anemia is BRIP1, in which biallelic truncating mutations lead to Fanconi anemia group J and monoallelic truncating mutations predispose to certain cancers. However, of the more than 1000 reported missense mutations in BRIP1, very few have been functionally characterized. We evaluated the functional consequence of BRIP1 p.R848H (c.2543G &gt; A), which was homozygous in two cousins with low birth weight, microcephaly, upper limb abnormalities, and imperforate anus and for whom chromosome breakage analysis of patient cells revealed increased mitomycin C sensitivity. BRIP1 p.R848H alters a highly conserved residue in the catalytic DNA helicase domain. We show that BRIP1 p.R848H leads to a defect in helicase activity. Heterozygosity at this missense has been reported in multiple cancer patients but, in the absence of functional studies, classified as of unknown significance. Our results support that this mutation is pathogenic for Fanconi anemia in homozygotes and for increased cancer susceptibility in heterozygous carriers

Genomic analysis of inherited hearing loss in the Palestinian population

The genetic characterization of a common phenotype for an entire population reveals both the genetic epidemiology of that phenotype and the power of family-based, population-wide genomic analysis. We characterized the genetics of hearing loss throughout the Palestinian population of the West Bank and Gaza. In families with no prior history of hearing loss, we estimate that 56% of hearing loss is genetic and 44% is not genetic. For most families with inherited hearing loss, causal genes and mutations were identified. Most inherited hearing loss in the population was attributable to consanguinity. Given the ongoing decline in consanguineous marriage, inherited hearing loss will likely be much rarer in the next generation