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BACKGROUND: The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex. RESULTS: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02-5.61, P = 1.1E-03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status. CONCLUSIONS: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia.
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Metilación de ADN , Esquizofrenia , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Envejecimiento/genética , Senescencia Celular , Epigénesis Genética , Esquizofrenia/genéticaRESUMEN
Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.
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Trastorno Depresivo Mayor , Estudio de Asociación del Genoma Completo , Humanos , Predisposición Genética a la Enfermedad , Trastorno Depresivo Mayor/genética , Depresión , Mapeo Cromosómico , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND AND HYPOTHESIS: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. STUDY DESIGN: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. STUDY RESULTS: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores. CONCLUSIONS: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.
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Trastorno Bipolar , Trastornos Psicóticos , Esquizofrenia , Humanos , Endofenotipos , Trastornos Psicóticos/genética , Trastornos Psicóticos/complicaciones , Esquizofrenia/genética , Esquizofrenia/complicaciones , Trastorno Bipolar/genética , Trastorno Bipolar/complicaciones , Herencia Multifactorial/genética , Factores de Riesgo , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: It remains unclear how adverse childhood experiences (ACE) and increased genetic risk for bipolar disorder (BD) interact to influence BD symptom outcomes. Here we calculated multiple psychiatric polygenic risk scores (PRS) and used the measures of ACE to understand these gene-environment interactions. METHOD: 885 BD subjects were included for analyses. BD, ADHD, MDD and SCZ PRSs were calculated using the PRS-CS-auto method. ACEs were evaluated using the Children Life Event Questionnaire (CLEQ). Participants were divided into groups based on the presence of ACE and the total number of ACEs. The associations between total ACE number, PRSs and their interactions were evaluated using multiple linear and logistic regressions. Secondary analyses were performed to evaluate the influence of ACE and PRS on sub-phenotypes of BD. RESULTS: The number of ACEs increased with the ADHD PRS. BD participants who had ACEs showed an earlier age of BD onset and higher odds of having rapid cycling. Increased BD PRS was associated with increased odds of developing psychotic symptoms. Higher ADHD PRS was associated with increased odds of having rapid cycling. No prediction effect was observed from MDD and SCZ PRS. And, we found no significant interaction between ACE numbers and any of the PRSs in predicting any selected BD sub-phenotypes. LIMITATIONS: The study was limited by sample size, ACE definition, and cross-sectional data collection method. CONCLUSIONS: The findings consolidate the importance of considering multiple psychiatric PRSs in predicting symptom outcomes among BD patients.
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Experiencias Adversas de la Infancia , Trastorno Bipolar , Niño , Humanos , Trastorno Bipolar/epidemiología , Trastorno Bipolar/genética , Estudios Transversales , Factores de Riesgo , Interacción Gen-AmbienteRESUMEN
BACKGROUND: Increased rates of visual impairment are observed in people with schizophrenia. AIMS: We assessed whether genetically predicted poor distance acuity is causally associated with schizophrenia, and whether genetically predicted schizophrenia is causally associated with poorer visual acuity. METHOD: We used bidirectional, two-sample Mendelian randomisation to assess the effect of poor distance acuity on schizophrenia risk, poorer visual acuity on schizophrenia risk and schizophrenia on visual acuity, in European and East Asian ancestry samples ranging from approximately 14 000 to 500 000 participants. Genetic instrumental variables were obtained from the largest available summary statistics: for schizophrenia, from the Psychiatric Genomics Consortium; for visual acuity, from the UK Biobank; and for poor distance acuity, from a meta-analysis of case-control samples. We used the inverse variance-weighted method and sensitivity analyses to test validity of results. RESULTS: We found little evidence that poor distance acuity was causally associated with schizophrenia (odds ratio 1.00, 95% CI 0.91-1.10). Genetically predicted schizophrenia was associated with poorer visual acuity (mean difference in logMAR score: 0.024, 95% CI 0.014-0.033) in European ancestry samples, with a similar but less precise effect that in smaller East Asian ancestry samples (mean difference: 0.186, 95% CI -0.008 to 0.379). CONCLUSIONS: Genetic evidence supports schizophrenia being a causal risk factor for poorer visual acuity, but not the converse. This highlights the importance of visual care for people with psychosis and refutes previous hypotheses that visual impairment is a potential target for prevention of schizophrenia.
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BACKGROUND: Genetic Risk Scores (GRS) for predicting dementia risk have mostly been used in people of European ancestry with limited testing in other ancestry groups. METHODS: We conducted a logistic regression with all-cause dementia as the outcome and z-standardised GRS as the exposure across diverse ethnic groups. FINDINGS: There was variation in frequency of APOE alleles across ethnic groups. Per standard deviation (SD) increase in z-GRS including APOE, the odds ratio (OR) for dementia was 1.73 (95%CI 1.69-1.77). Z-GRS excluding APOE also increased dementia risk (OR 1.21 per SD increase, 95% CI 1.18-1.24) and there was no evidence that ethnicity modified this association. Prediction of secondary outcomes was less robust in those not of European ancestry when APOE was excluded from the GRS. INTERPRETATION: z-GRS derived from studies in people of European ancestry can be used to quantify genetic risk in people from more diverse ancestry groups. Urgent work is needed to include people from diverse ancestries in future genetic risk studies to make this field more inclusive.
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Bancos de Muestras Biológicas , Demencia , Humanos , Demencia/epidemiología , Demencia/genética , Factores de Riesgo , Reino Unido/epidemiologíaRESUMEN
We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.
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Trastorno Bipolar , Esquizofrenia , Proteínas de Anclaje a la Quinasa A/genética , Trastorno Bipolar/genética , Exoma/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Esquizofrenia/genética , Secuenciación del ExomaRESUMEN
INTRODUCTION: Few longitudinal studies have explored the association between apolipoprotein E gene (APOE) status, sleep disturbances, and incident dementia among middle-aged participants. METHODS: Cox regression analyses explored the association of sleep duration, insomnia, and daytime napping with incident all-cause dementia and their interaction with APOE genetic risk among 397,777 middle-aged adults. RESULTS: During a median of 10.8 years follow-up, sleeping more or fewer than 7 hours was associated with a higher dementia risk (hazard ratio [HR] for 5 vs 7 hours: 1.35, 95% confidence interval [CI] 1.11-1.64; HR for 9 vs 7 hours: 1.59; 95% CI 1.37-1.85) as was daytime napping (HR for often/all of the time vs never/rarely: 1.67; 95% CI 1.37-2.03). Stratified analyses revealed that the effects of sleep disturbances were similar across all APOE genetic risk groups. DISCUSSION: Short and long sleep duration and daytime napping in middle-aged individuals are associated with the development of dementia in later life. Sleep duration and quality are important for everyone regardless of their genetic risk by APOE genotype.
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Demencia , Trastornos del Sueño-Vigilia , Adulto , Apolipoproteínas E/genética , Demencia/epidemiología , Demencia/genética , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Factores de Riesgo , Sueño , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/genéticaRESUMEN
Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression. Design, Setting, and Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021. Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts. Main Outcomes and Measures: Depression status was defined based on health records and self-report questionnaires. Results: There were a total of 194â¯548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15â¯771 individuals with depression and 178â¯777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (ß = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (ß = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (ß = -0.003, SE = 0.005, P = .53 for rs4656484 and ß = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent. Conclusions and Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.
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Pueblo Asiatico/genética , Depresión/genética , Trastorno Depresivo/genética , Estudio de Asociación del Genoma Completo , Adulto , Pueblo Asiatico/etnología , Depresión/etnología , Trastorno Depresivo/etnología , Asia Oriental/etnología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Población Blanca/genéticaRESUMEN
We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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Metilación de ADN , Epigenoma , Trastornos Psicóticos/fisiopatología , Esquizofrenia Resistente al Tratamiento/fisiopatología , Adulto , Anciano , Inglaterra , Femenino , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/genética , Esquizofrenia Resistente al Tratamiento/genética , Escocia , Suecia , Adulto JovenRESUMEN
BACKGROUND: Communication of mild cognitive impairment (MCI) diagnoses is challenging due to its heterogeneity and unclear prognosis. AIM: To identify how MCI is communicated and to explore the relationship with patient and companion understanding. METHOD: Conversation analysis identified whether MCI was named and explained in 43 video recorded diagnosis feedback meetings. Afterward, patients and companions were asked to name the diagnosis to assess understanding. RESULTS: Mild cognitive impairment was not named in 21% meetings. Symptoms were explained as (a) a result of vascular conditions (49%), (b) a stage between normal ageing and dementia (30%), or (c) caused by psychological factors (21%). Fifty-four percentage of prognosis discussions included mention of dementia. There was no association between symptom explanations and whether prognosis discussions included dementia. Fifty-seven percentage patients and 37% companions reported not having or not knowing their diagnosis after the meeting. They were more likely to report MCI when prognosis discussions included dementia. CONCLUSIONS: Doctors offer three different explanations of MCI to patients. The increased risk of dementia was not discussed in half the diagnostic feedback meetings. This is likely to reflect the heterogeneity in the definition, cause and likely prognosis of MCI presentations. Clearer and more consistent communication, particularly about the increased risk of dementia, may increase patient understanding and enable lifestyle changes to prevent some people progressing to dementia.
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Disfunción Cognitiva , Disfunción Cognitiva/diagnóstico , Comunicación , Progresión de la Enfermedad , Humanos , PronósticoRESUMEN
BACKGROUND: Observational studies indicate that approximately a third of dementia cases are attributable to modifiable cardiometabolic, physical and mental health, and social and lifestyle risk factors. There is evidence that intensive behaviour change interventions targeting these factors can reduce cognitive decline. [Figure: see text] METHODS AND ANALYSIS: We will design and test a low intensity, secondary dementia-prevention programme (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline, "APPLE-Tree") to slow cognitive decline in people with subjective cognitive decline with or without objective cognitive impairment. We will embed our work within social science research to understand how dementia prevention is currently delivered and structured. We will carry out systematic reviews and around 50 qualitative interviews with stakeholders, using findings to coproduce the APPLE-Tree intervention. We plan a 10-session group intervention, involving personalised goal-setting, with individual sessions for those unable or unwilling to attend groups, delivered by psychology assistants who will be trained and supervised by clinical psychologists. The coproduction group (including public and patient involvement [PPI], academic and clinical/third-sector professional representatives) will use the Behaviour Change Wheel theoretical framework to develop it. We will recruit and randomly allocate 704 participants, 1:1 to the intervention: informational control group. This sample size is sufficient to detect a between-group difference at 2 years of 0.15 on the primary outcome (cognition: modified neuropsychological test battery; 90% power, 5% significance, effect size 0.25, SD 0.6). DISSEMINATION: We will work with Public Health England and third-sector partners to produce an effective national implementation approach, so that if our intervention works, it is used in practice.
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Demencia , Malus , Cognición , Demencia/prevención & control , Inglaterra , Humanos , Estilo de Vida , Tecnología , ÁrbolesRESUMEN
BACKGROUND: there is little research on how people with dementia are involved in treatment decisions at diagnosis. OBJECTIVE: to measure shared decision making when starting cholinesterase inhibitors, investigate associations with contextual factors and explore satisfaction and experience of the diagnostic meeting. SETTING: nine UK memory clinics in two geographical locations. SUBJECTS: 74 people receiving dementia diagnoses (with 69 companions) and 21 doctors. METHODS: we video-recorded 74 memory clinic consultations and rated doctor-shared decision making behaviours using the Observing Patient Involvement in Decision Making scale (OPTION-5 scale). Patients and companions rated their satisfaction and experience. Mixed-effects regressions investigated involvement and (i) number people present, meeting length, capacity, cognitive functioning, diagnosis; and (ii) patient/companion satisfaction and consultation experience. RESULTS: mean consultation time was 26.7 min. Mean OPTION-5 score was 22.5/100 (Standard Deviation = 17.3). Doctors involved patients in decisions more often when patients had mixed dementia (ß = 10.13, 95% confidence interval 1.25-19.0, P = 0.025) and in shorter meetings (ß = -0.51, 95% CI -0.87 to -0.15, P = 0.006). Patient and companion satisfaction were high and not associated with whether doctors invited patient involvement. Half of patients and one-third companions were uncertain about the meeting outcome, experienced communication barriers and negative emotions. CONCLUSIONS: consultations scored low on shared decision making, but were comparable to other settings and were not lower with more cognitively impaired patients. Negative patient and companion experiences reflect the importance of supporting healthcare providers to address patient and companion emotions and need for information.
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Inhibidores de la Colinesterasa/uso terapéutico , Cognición/fisiología , Toma de Decisiones Conjunta , Demencia/diagnóstico , Participación del Paciente/tendencias , Satisfacción del Paciente , Relaciones Médico-Paciente , Médicos/psicología , Adulto , Anciano , Anciano de 80 o más Años , Demencia/tratamiento farmacológico , Demencia/psicología , Emociones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Derivación y ConsultaRESUMEN
BACKGROUND: Shared decision-making is advocated but may be affected by cognitive impairment. Measures of shared decision-making provide global descriptions of communication without detailed analysis of the subtle ways in which doctors invite patient input.AimsWe aimed to explore medication decisions in dementia, using a standardised Treatment Recommendation Coding Scheme. METHOD: We analysed 71 video-recorded dementia diagnostic meetings from nine memory clinics. Recommendations were coded as pronouncements ('I will start you on medication'), proposals ('Shall we try medication?'), suggestions ('Would you like to try medication?'), offers ('I can prescribe medication') or assertions ('There is medication'). Patient responses were coded as acceptance ('I'd like to have that'), active resistance ('I'm not very keen') and passive resistance (minimal or no response). Cognitive test scores, prescription rates and satisfaction were assessed and associations were explored. RESULTS: Doctors used suggestions in 42% of meetings, proposals in 25%, assertions in 13%, pronouncements in 11% and offers in 9%. Over 80% of patients did not indicate clear acceptance. Patients were most likely to actively resist after suggestions. There was no association between cognitive impairment and recommendation format. Patients were less satisfied with pronouncements. Patient preference did not influence whether medication was prescribed. CONCLUSIONS: Doctors initially nominate people with dementia as the decision maker, and this is unaffected by cognitive impairment. Over 80% of patients resisted starting medication, mostly through passive resistance, the most common form of disagreement in communication. Medication still tended to be prescribed, indicating that factors other than patient preference affect prescription.Declarations of interestNone.
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Toma de Decisiones , Demencia/terapia , Participación del Paciente , Prioridad del Paciente , Anciano , Anciano de 80 o más Años , Comunicación , Prescripciones de Medicamentos , Femenino , Humanos , Masculino , Satisfacción del Paciente , Relaciones Médico-PacienteRESUMEN
PURPOSE OF REVIEW: Investigation for genetic causes of intellectual disability has advanced rapidly in recent years. We review the assessment of copy number variants (CNVs) and the use of next-generation sequencing based assays to identify single nucleotide variation in intellectual disability. We discuss the diagnostic yields that can be expected with the different assays. There is high co-morbidity of intellectual disability and psychiatric disorders. We review the relationship between variants which are pathogenic for intellectual disability and the risk of child and adolescent onset psychiatric disorders. RECENT FINDINGS: The diagnostic yields from genome wide CNV analysis and whole exome sequence analysis are high - in the region of 15 and 40%, respectively - but vary according to exact referral criteria. Many variants pathogenic for intellectual disability, notably certain recurrent CNVs, have emerged as strong risk factors for other neurodevelopmental disorders such as autism spectrum disorders, attention deficit hyperactivity disorder, and schizophrenia. SUMMARY: It is now conceivable that etiological variants could be identified in the majority of children presenting with intellectual disability using next-generation sequencing based assays. However, challenges remain in assessment of the pathogenicity of variants, reporting of incidental findings in children and determination of prognosis, particularly in relation to psychiatric disorders.
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Variaciones en el Número de Copia de ADN , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Adolescente , Niño , HumanosRESUMEN
BACKGROUND: Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.AimsTo determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders. METHOD: A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites. RESULTS: The yield of pathogenic CNVs was high - 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations. CONCLUSIONS: In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.Declaration of interestNone.
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Trastornos Generalizados del Desarrollo Infantil/genética , Variaciones en el Número de Copia de ADN/genética , Discapacidad Intelectual/genética , Trastornos Mentales/genética , Esquizofrenia/genética , Adulto , Trastornos Generalizados del Desarrollo Infantil/epidemiología , Comorbilidad , Europa (Continente)/epidemiología , Femenino , Humanos , Discapacidad Intelectual/epidemiología , Masculino , Trastornos Mentales/epidemiología , Análisis por Micromatrices , Persona de Mediana Edad , Esquizofrenia/epidemiologíaRESUMEN
Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.
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Cromosomas Humanos Par 2/genética , Discapacidades del Desarrollo/genética , Trastornos Mentales/genética , Adolescente , Adulto , Niño , Preescolar , Aberraciones Cromosómicas , Deleción Cromosómica , Duplicación Cromosómica , Variaciones en el Número de Copia de ADN/genética , Femenino , Duplicación de Gen/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Fenotipo , Reino UnidoRESUMEN
BACKGROUND: Dementia diagnosis rates are increasing. Guidelines recommend that people with dementia should be told their diagnosis clearly and honestly to facilitate future planning. Aims To analyse how doctors deliver a dementia diagnosis in practice. METHOD: Conversation analysis was conducted on 81 video-recorded diagnosis feedback meetings with 20 doctors from nine UK memory clinics. RESULTS: All doctors named dementia; 59% (n = 48) approached the diagnosis indirectly but delicately ('this is dementia') and 41% (n = 33) approached this directly but bluntly ('you have Alzheimer's disease'). Direct approaches were used more often with people with lower cognitive test scores. Doctors emphasised that the dementia was mild and tended to downplay its progression, with some avoiding discussing prognosis altogether. CONCLUSIONS: Doctors are naming dementia to patients. Direct approaches reflect attempts to ensure clear diagnosis. Downplaying and avoiding prognosis demonstrates concerns about preserving hope but may compromise understanding about and planning for the future. Declaration of interest None.
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Demencia/diagnóstico , Relaciones Médico-Paciente , Revelación de la Verdad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atención Secundaria de Salud , Reino Unido , Grabación en VideoRESUMEN
BACKGROUND: An increasing number of genetic causes of intellectual disabilities (ID) are identifiable by clinical genetic testing, offering the prospect of bespoke patient management. However, little is known about the practices of psychiatrists and their views on genetic testing. METHOD: We undertook an online survey of 215 psychiatrists, who were contacted via the Royal College of Psychiatrist's Child and Adolescent and Intellectual Disability Psychiatry mailing lists. RESULTS: In comparison with child and adolescent psychiatrists, intellectual disability psychiatrists ordered more genetic tests, referred more patients to genetic services, and were overall more confident in the genetic testing process. Respondents tended to agree that genetic diagnoses can help patient management; however, management changes were infrequently found in clinical practice. CONCLUSIONS: Differences are apparent in the existing views and practices of child and adolescent and intellectual disability psychiatrists. Developing training and collaboration with colleagues working in genetic services could help to reduce discrepancies and improve clinical practice.