Multiple psychiatric polygenic risk scores predict associations between childhood adversity and bipolar disorder

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

Effects of task oriented conflict of inter-subgroups on information exchange in group decision making

The purpose of this study was to examine the effects of task oriented conflict of inter-sub-groups on pooling of unshared information and information exchange between members, on cognition of information, and on perception in group decision making. The subjects were 30 female nursing school students. They discussed the flictious selection of a sub-chiefnurse in a group consisting of five members. Information about fictitious candidates (candidate A and candidate B) was given to the group members before discussion and consisted of shared information and unshared information. Information were positive, negative and neutral as classfied by preliminary study. In advance one groups were considered of two followers who believed that candidate A was qualified, and the other two who believed that candidate B was qualified (henceforth task-oriented conflict condition) and the other were considered of all four followers who believed that candidate A was qualified. The results were as follows: (1) Unshared information was more conveyed and neutral information was less interpreted and conveyed in task-oriented conflict condition. (2) Followers had more negative evaluations of the leader, the followers, and the discussion in task oriented conflict condition. The results were discussed from the point of view of the nature of task oriented conflict, group goal, and quality of information exchange.

Involving patients with dementia in decisions to initiate treatment:Effect on patient acceptance, satisfaction and medication prescription

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. AIMS: We 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 INTEREST: None

Patient and companion concerns when receiving a dementia diagnosis: an observational study of dementia diagnosis feedback meetings

Receiving a diagnosis of dementia is a life-changing event and can cause strong emotional reactions. The aim of this study was to examine patient and companion concerns expressed during dementia diagnosis feedback meetings. Sixty consultations between 19 health-care professionals (HCPs), 60 patients and 59 companions were video-recorded and transcribed. Concerns were identified from the transcripts and were (a) content analysed, (b) coded as elicited by the HCP or volunteered by the patient or companion, and (c) coded according to whether the HCP encouraged or discouraged elaboration of the concern. A total of 249 concerns were identified (average four concerns per consultation). There were three areas of findings: (a) patients and companions were concerned about the symptoms of dementia and receiving a diagnosis; other concerns related to patients’ mental and physical health, and prognosis, (b) HCPs elicited more patient than companion concerns and mostly elicited concerns aligned with the agenda of diagnosis feedback, and (c) HCPs were more likely to encourage elaboration when they elicited the concern. Nearly 40 per cent of concerns were discouraged by the HPC changing topic, with concerns about prognosis most commonly discouraged. The findings suggest that there were a wide variety of concerns at dementia diagnosis, many extending beyond the experience of dementia symptoms. HCP avoidance of concerns about prognosis demonstrated delicacy in discussing the deteriorating course of dementia

Investigating the association between schizophrenia and distance visual acuity: Mendelian randomisation study

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

The role of thyroid function in borderline personality disorder and schizophrenia:a Mendelian Randomisation study

Background: Genome-wide association studies have reported a genetic overlap between borderline personality disorder (BPD) and schizophrenia (SCZ). Epidemiologically, the direction and causality of the association between thyroid function and risk of BPD and SCZ are unclear. We aim to test whether genetically predicted variations in TSH and FT4 levels or hypothyroidism are associated with the risk of BPD and SCZ. Methods: We employed Mendelian Randomisation (MR) analyses using genetic instruments associated with TSH and FT4 levels as well as hypothyroidism to examine the effects of genetically predicted thyroid function on BPD and SCZ risk. Bidirectional MR analyses were employed to investigate a potential reverse causal association. Results: Genetically predicted higher FT4 was not associated with the risk of BPD (OR: 1.18; P = 0.60, IVW) or the risk of SCZ (OR: 0.93; P = 0.19, IVW). Genetically predicted higher TSH was not associated with the risk of BPD (OR: 1.11; P = 0.51, IVW) or SCZ (OR: 0.98, P = 0.55, IVW). Genetically predicted hypothyroidism was not associated with BPD or SCZ. We found no evidence for a reverse causal effect between BPD or SCZ on thyroid function. Conclusions: We report evidence for a null association between genetically predicted FT4, TSH or hypothyroidism with BPD or SCZ risk. There was no evidence for reverse causality.</p

Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk

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.</p

Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk

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.</p

Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing

Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer

Chromosomal microarray testing in adults with intellectual disability presenting with comorbid psychiatric disorders.

Chromosomal copy-number variations (CNVs) are a class of genetic variants highly implicated in the aetiology of neurodevelopmental disorders, including intellectual disabilities (ID), schizophrenia and autism spectrum disorders (ASD). Yet the majority of adults with idiopathic ID presenting to psychiatric services have not been tested for CNVs. We undertook genome-wide chromosomal microarray analysis (CMA) of 202 adults with idiopathic ID recruited from community and in-patient ID psychiatry services across England. CNV pathogenicity was assessed using standard clinical diagnostic methods and participants underwent comprehensive medical and psychiatric phenotyping. We found an 11% yield of likely pathogenic CNVs (22/202). CNVs at recurrent loci, including the 15q11-q13 and 16p11.2-p13.11 regions were most frequently observed. We observed an increased frequency of 16p11.2 duplications compared with those reported in single-disorder cohorts. CNVs were also identified in genes known to effect neurodevelopment, namely NRXN1 and GRIN2B. Furthermore deletions at 2q13, 12q21.2-21.31 and 19q13.32, and duplications at 4p16.3, 13q32.3-33.3 and Xq24-25 were observed. Routine CMA in ID psychiatry could uncover ~11% new genetic diagnoses with potential implications for patient management. We advocate greater consideration of CMA in the assessment of adults with idiopathic ID presenting to psychiatry services