Genome-wide association study identifies new loci associated with OCD.

To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS meta-analysis with a 2-3-fold increase in case sample size (OCD cases: N = 37,015, controls: N = 948,616) compared to the last OCD GWAS, including six previously published cohorts (OCGAS, IOCDF-GC, IOCDF-GC-trio, NORDiC-nor, NORDiC-swe, and iPSYCH) and unpublished self-report data from 23andMe Inc. We explored the genetic architecture of OCD by conducting gene-based tests, tissue and celltype enrichment analyses, and estimating heritability and genetic correlations with 74 phenotypes. To examine a potential heterogeneity in our data, we conducted multivariable GWASs with MTAG. We found support for 15 independent genome-wide significant loci (14 new) and 79 protein-coding genes. Tissue enrichment analyses implicate multiple cortical regions, the amygdala, and hypothalamus, while cell type analyses yielded 12 cell types linked to OCD (all neurons). The SNP-based heritability of OCD was estimated to be 0.08. Using MTAG we found evidence for specific genetic underpinnings characteristic of different cohort-ascertainment and identified additional significant SNPs. OCD was genetically correlated with 40 disorders or traits-positively with all psychiatric disorders and negatively with BMI, age at first birth and multiple autoimmune diseases. The GWAS meta-analysis identified several biologically informative genes as important contributors to the aetiology of OCD. Overall, we have begun laying the groundwork through which the biology of OCD will be understood and described.

Exploring the relationship between attributional style measured in virtual reality and bullying among children at familial high risk of schizophrenia or bipolar disorder compared with controls.

BACKGROUND: Children of parents with severe mental illness report bullying more often compared with controls. We hypothesized that deviations in attributional styles may explain the increased prevalence of bullying experiences. We aimed to assess real-time responses to standardized ambiguous social situations, bullying experiences by children, their primary caregivers, and teachers, and to investigate potential associations between attributional styles and bullying. METHOD: The study included 465 children aged 11-12, born to parents with schizophrenia, N =179, bipolar disorder, N = 105, or population-based controls, N = 181. Attributional style was evaluated using virtual reality environments depicting ambiguous social everyday situations. We created a tailored assessment since no suitable assessments were found. Bullying was assessed through self-reports and reports from primary caregivers and teachers. RESULTS: We observed no group differences in the attributional style of the children. Reports from children, primary caregivers, and teachers revealed that compared with controls, children born to parents with schizophrenia were more likely to perceive bullying victimization, with high consistency among reports. No associations were found between bullying reports and attributional style. CONCLUSIONS: Children of parents with schizophrenia consistently experienced more bullying, as reported by the children themselves, primary caregivers, and teachers. No differences in attributional style were found, indicating that attributional style did not explain the increased prevalence of bullying reports. While it cannot be ruled out that our virtual environments were insufficient to trigger a sense of social exclusion, the results suggest that the observed differences in reported bullying are genuine and not a result of the child's attributional style.

The development in rating-based executive functions in children at familial high risk of schizophrenia or bipolar disorder from age 7 to age 11: the Danish high risk and resilience study.

Executive functions (EF) deficits are well documented in children at familial high risk of schizophrenia (FHR-SZ), and to a lesser degree in children at familial high risk of bipolar disorder (FHR-BP). The aim of this study was to assess EF development in preadolescent children at FHR-SZ, FHR-BP and population-based controls (PBC) using a multi-informant rating scale. A total of 519 children (FHR-SZ, n = 201; FHR-BP, n = 119; PBC, n = 199) participated at age 7, at age 11 or at both time points. Caregivers and teachers completed the Behavior Rating Inventory of Executive Functions (BRIEF). The developmental pattern from age 7 to age 11, did not differ between groups. At age 11, caregivers and teachers rated children at FHR-SZ as having widespread EF deficits. A higher proportion of children at FHR-SZ had clinically significant scores on the General executive composite (GEC) and all BRIEF indices compared to PBC. According to the caregivers, children at FHR-BP had significantly more EF deficits than PBC on 9 out of 13 BRIEF scales, whereas according to teachers, they only had significantly more deficits on one subdomain (Initiate). Likewise, caregivers rated a significantly higher proportion of children at FHR-BP above the clinical cut-off on the GEC and Metacognition index, compared to PBC, whereas there were no significant differences according to teachers. This study highlights the relevance of including multi-informant rating scales in the assessment of EF in children at FHR-SZ and FHR-BP. The results imply a need to identify children at high risk who would benefit from targeted intervention.

Children at Familial High risk of Schizophrenia and Bipolar Disorder Exhibit Altered Connectivity Patterns During Pre-attentive Processing of an Auditory Prediction Error.

BACKGROUND AND HYPOTHESIS: Individuals with schizophrenia or bipolar disorder have attenuated auditory mismatch negativity (MMN) responses, indicating impaired sensory information processing. Computational models of effective connectivity between brain areas underlying MMN responses show reduced connectivity between fronto-temporal areas in individuals with schizophrenia. Here we ask whether children at familial high risk (FHR) of developing a serious mental disorder show similar alterations. STUDY DESIGN: We recruited 67 children at FHR for schizophrenia, 47 children at FHR for bipolar disorder as well as 59 matched population-based controls from the Danish High Risk and Resilience study. The 11-12-year-old participants engaged in a classical auditory MMN paradigm with deviations in frequency, duration, or frequency and duration, while we recorded their EEG. We used dynamic causal modeling (DCM) to infer on the effective connectivity between brain areas underlying MMN. STUDY RESULTS: DCM yielded strong evidence for differences in effective connectivity among groups in connections from right inferior frontal gyrus (IFG) to right superior temporal gyrus (STG), along with differences in intrinsic connectivity within primary auditory cortex (A1). Critically, the 2 high-risk groups differed in intrinsic connectivity in left STG and IFG as well as effective connectivity from right A1 to right STG. Results persisted even when controlling for past or present psychiatric diagnoses. CONCLUSIONS: We provide novel evidence that connectivity underlying MMN responses in children at FHR for schizophrenia and bipolar disorder is altered at the age of 11-12, echoing findings that have been found in individuals with manifest schizophrenia.

Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a complex disorder that manifests variability in long-term outcomes and clinical presentations. The genetic contributions to such heterogeneity are not well understood. Here we show several genetic links to clinical heterogeneity in ADHD in a case-only study of 14,084 diagnosed individuals. First, we identify one genome-wide significant locus by comparing cases with ADHD and autism spectrum disorder (ASD) to cases with ADHD but not ASD. Second, we show that cases with ASD and ADHD, substance use disorder and ADHD, or first diagnosed with ADHD in adulthood have unique polygenic score (PGS) profiles that distinguish them from complementary case subgroups and controls. Finally, a PGS for an ASD diagnosis in ADHD cases predicted cognitive performance in an independent developmental cohort. Our approach uncovered evidence of genetic heterogeneity in ADHD, helping us to understand its etiology and providing a model for studies of other disorders.

Polygenic Risk of Mental Disorders and Subject-Specific School Grades.

BACKGROUND: Education is essential for socioeconomic security and long-term mental health; however, mental disorders are often detrimental to the educational trajectory. Genetic correlations between mental disorders and educational attainment do not always align with corresponding phenotypic associations, implying heterogeneity in the genetic overlap. METHODS: We unraveled this heterogeneity by investigating associations between polygenic risk scores for 6 mental disorders and fine-grained school outcomes: school grades in language and mathematics in ninth grade and high school, as well as educational attainment by age 25, using nationwide-representative data from established cohorts (N = 79,489). RESULTS: High polygenic liability of attention-deficit/hyperactivity disorder was associated with lower grades in language and mathematics, whereas high polygenic risk of anorexia nervosa or bipolar disorder was associated with higher grades in language and mathematics. Associations between polygenic risk and school grades were mixed for schizophrenia and major depressive disorder and neutral for autism spectrum disorder. CONCLUSIONS: Polygenic risk scores for mental disorders are differentially associated with language and mathematics school grades.

Treatment of schizophrenia evaluated via the pharmacopsychometric triangle-An integrative approach with emphasis on well-being and functioning.

Quantification of treatment response is crucial to optimize outcomes for patients with schizophrenia. In this study, we evaluated the relationship between quantitative measures of clinician-rated symptom severity and self-rated side effects, well-being, and functioning among inpatients with schizophrenia using the six-item version of the Positive and Negative Syndrome Scale (PANSS-6), the Glasgow Antipsychotic Side-effect Scale (GASS), the WHO-Five Well-being Index (WHO-5), and the Sheehan Disability Scale (SDS). All measurements were conducted as close to admission and discharge as possible. Well-being and functioning were found to be most strongly associated with the additive effect of symptoms and side effects, while changes in side effects, well-being, and functioning appeared to be relatively independent from changes in symptom severity. The use of both symptom and side effect measures should inform clinical decision-making in the treatment of schizophrenia, as it has the potential to optimize functioning and well-being.

The correlates of neonatal complement component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders.

Complement components have been linked to schizophrenia and autoimmune disorders. We examined the association between neonatal circulating C3 and C4 protein concentrations in 68,768 neonates and the risk of six mental disorders. We completed genome-wide association studies (GWASs) for C3 and C4 and applied the summary statistics in Mendelian randomization and phenome-wide association studies related to mental and autoimmune disorders. The GWASs for C3 and C4 protein concentrations identified 15 and 36 independent loci, respectively. We found no associations between neonatal C3 and C4 concentrations and mental disorders in the total sample (both sexes combined); however, post-hoc analyses found that a higher C3 concentration was associated with a reduced risk of schizophrenia in females. Mendelian randomization based on C4 summary statistics found an altered risk of five types of autoimmune disorders. Our study adds to our understanding of the associations between C3 and C4 concentrations and subsequent mental and autoimmune disorders.

Postpartum and non-postpartum depression: a population-based matched case-control study comparing polygenic risk scores for severe mental disorders.

It remains inconclusive whether postpartum depression (PPD) and depression with onset outside the postpartum period (MDD) are genetically distinct disorders. We aimed to investigate whether polygenic risk scores (PGSs) for major mental disorders differ between PPD cases and MDD cases in a nested case-control study of 50,057 women born from 1981 to 1997 in the iPSYCH2015 sample in Demark. We identified 333 women with first-onset postpartum depression (PPD group), who were matched with 993 women with first-onset depression diagnosed outside of postpartum (MDD group), and 999 female population controls. Data on genetics and depressive disorders were retrieved from neonatal biobanks and the Psychiatric Central Research Register. PGSs were calculated from both individual-level genetic data and meta-analysis summary statistics from the Psychiatric Genomics Consortium. Conditional logistic regression was used to calculate the odds ratio (OR), accounting for the selection-related reproductive behavior. After adjustment for covariates, higher PGSs for severe mental disorders were associated with increased ORs of both PPD and MDD. Compared with MDD cases, MDD PGS and attention-deficit/hyperactivity disorder PGS were marginally but not statistically higher for PPD cases, with the OR of PPD versus MDD being 1.12 (95% CI: 0 .97-1.29) and 1.11 (0.97-1.27) per-standard deviation increase, respectively. The ORs of PPD versus MDD did not statistically differ by PGSs of bipolar disorder, schizophrenia, or autism spectrum disorder. Our findings suggest that relying on PGS data, there was no clear evidence of distinct genetic make-up of women with depression occurring during or outside postpartum, after taking the selection-related reproductive behavior into account.

Pubertal timing, sex hormone levels, and associations between early life adversity and accelerated development amongst 11-year-old children of parents with schizophrenia or bipolar disorder and controls: The Danish high risk and Resilience study via 11.

Background: Children of parents with severe mental illness have several known risk factors for altered pubertal timing. Pubertal timing is important for children's physical and emotional development. We aimed to examine pubertal timing and associations between pubertal timing, early life adversity and child problem behavior including psychiatric diagnoses among children of parents with schizophrenia or bipolar disorder and controls. Methods: Self-reported Tanner stage (mean age 11.9, range 10.87-12.67), sex hormone levels, home environment, placement out of home, and problem behavior including psychiatric diagnoses of children at familial high-risk (FHR) of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP) and population-based controls (PBC) were assessed. Results: A total of 465 children participated in the study (Tanner assessment N = 417, sex hormones N = 293). Assessed with self-reported Tanner, no difference in pubertal timing was found between groups (p = 0.09). Hormone levels did not differ between groups except for inhibin B (mean (SD) = 55.86 (29.13) pg/mL for FHR-SZ girls vs 84.98 (47.98) pg/mL) for PBC girls (p < 0.001)) and for follicle stimulating hormone (FSH) (mean (SD) = 5.82 (1.45) U/L for FHR-BP girls vs 4.54 (1.68) U/L for PBC girls (p < 0.001)). FHR children who were placed out of home (17 children, 3.8% of participants) had higher Tanner stages than those living at home (p < 0.001). Timing was not associated with level of problem behavior or psychiatric diagnoses. Conclusions: FHR children did not differ from controls in pubertal timing. Early life adversity assessed as placement out of home may be associated with accelerated pubertal timing among children of parents with schizophrenia or bipolar disorder.

Executive Control and Associated Brain Activity in Children With Familial High-Risk of Schizophrenia or Bipolar Disorder: A Danish Register-based Study.

BACKGROUND AND HYPOTHESES: Impaired executive control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired executive control as well as aberrant brain activation compared to population-based control (PBC) children. STUDY DESIGN: Using a flanker task, we examined executive control together with functional magnetic resonance imaging (fMRI) in 11- to 12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and PBC children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study-VIA 11. STUDY RESULTS: We included 85 (44% female) FHR-SZ, 63 (52% female) FHR-BP and 98 (50% female) PBC in the analyses. Executive control effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRT in FHR-BP and FHR-SZ compared to PBC (BF10 = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post hoc analyses excluding children with psychiatric illness yielded same results. CONCLUSION: FHR-SZ and FHR-BP at age 11-12 show intact ability to resolve a spatial visuomotor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk.

Development of social functioning in preadolescent children at familial high-risk of schizophrenia or bipolar disorder - a 4-year follow-up study from age 7 to 11.

Social functioning is a major indicator of psychosis risk and evidence is lacking regarding social functioning development during preadolescence in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP). We aimed to investigate development of social functioning from age 7 to 11 in children at FHR-SZ or FHR-BP compared with population-based controls. At 4-year follow-up, 179 children at FHR-SZ (mean age 12.0 y, SD 0.3), 105 children at FHR-BP (mean age 11.9 y, SD 0.2), and 181 controls (mean age 11.9 y, SD 0.2) participated. We used the Vineland-II to measure social functioning. Development of social functioning was non-significantly different across groups on the Socialization Composite score as well as the subscales Interpersonal Relations, Play and Leisure, and Coping Skills. At 4-year follow-up, children at FHR-SZ demonstrated impaired social functioning, whereas children at FHR-BP displayed social functioning comparable to controls except from impaired coping skills. From age 7 to 11, the maturational pace of social functioning in children at FHR-SZ and FHR-BP is parallel to that of controls. Children at FHR-SZ show stable social functioning deficits, whereas children at FHR-BP show normal social functioning except from emergence of discretely impaired coping skills at age 11.

Value of gym-based group exercise versus usual care for young adults receiving antipsychotic medication: study protocol for the multicenter randomized controlled Vega trial.

BACKGROUND: Exercise is recommended to protect physical health among people with severe mental illness and holds the potential to facilitate long-term recovery. An inclusive exercise community provides an opportunity for life skill training and social connectedness and may reduce the experience of loneliness and internalized stigmatization which together may improve personal recovery. Using a pragmatic randomized design, we aim to examine the effectiveness of a gym-based exercise intervention tailored to young adults in antipsychotic treatment (i.e., Vega Exercise Community) compared to usual care. It is hypothesized that the Vega Exercise Community will be superior to usual care for personal recovery at four months. METHODS: The trial will be conducted at four sites in Denmark from which 400 participants, aged 18 to 35 years, who are in current treatment with antipsychotic medications for the management of schizophrenia spectrum or affective disorders, will be recruited. Participants will be randomized (2:1) to Vega Exercise Community or usual care. Vega Exercise Community includes three weekly group-based exercise sessions hosted in commercial functional training centers delivered by certified Vega instructors. After four months, participants in Vega Exercise Community will be randomized (1:1) to minimal versus extended support with regards to sustained physical activity. Data will be collected at baseline, four, six and 12 months. The primary outcome is personal recovery assessed by Questionnaire about the Process of Recovery at four months. Behavioral symptoms, health-related quality of life, metabolic health, and program costs will be evaluated to further determine the effectiveness and cost-effectiveness of the Vega Exercise Community. Finally, the quality of life and physical and mental health of the participants' primary relative will be evaluated. DISCUSSION: The results of this trial may have important implications for health, sustained physical activity, and recovery for individuals in treatment with antipsychotics. Given the pragmatic design, positive results may readily be implemented by mental health care professionals to promote exercise as an integrated part of treatment of severe mental illness. TRIAL REGISTRATION: Clinical Trials.gov (NCT05461885, initial registration June 29th, 2022). WHO Universal Trial Number (UTN): U1111-1271-9928.

Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation.

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. The association of CYP2C19 and CYP2D6 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR=1.46, 95% CI [1.03, 2.06], p=0.033, heterogeneity I2=0%, subgroup difference p=0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19 and CYP2D6, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. CYP2D6 structural variants cannot be imputed from genotype data, limiting inference of pharmacogenetic effects. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses.

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

Attachment representations in 7-year-old children at familial high risk of schizophrenia or bipolar disorder: Associations with mental disorders and daily functioning: The Danish High Risk and Resilience Study, VIA 7-A population-based cohort study.

BACKGROUND: Attachment quality may affect psychological functioning. However, evidence on attachment representations and their correlates in children born to parents with schizophrenia and bipolar disorder is sparse. METHODS: We compared attachment representations in a Danish sample of 482 children aged 7 years at familial high risk of schizophrenia, bipolar disorder, and population-based controls and examined associations between attachment and mental disorders and daily functioning. Attachment representations were examined with the Story Stem Assessment Profile (SSAP). Mental disorders were ascertained in diagnostic interviews. Daily functioning was assessed with the Children's Global Assessment Scale. RESULTS: We found no between-group differences in attachment. Higher levels of secure attachment were associated with decreased risk of concurrent mental disorders in the schizophrenia high-risk group. Higher levels of insecure and disorganized attachment were associated with increased risk of mental disorders across the cohort. Higher levels of secure and insecure attachment were associated with better and poorer daily functioning, respectively. In the current study, results regarding defensive avoidance could not be reported due to methodological limitations. CONCLUSION: Familial high risk of schizophrenia (FHR-SZ) or bipolar disorder is not associated with less secure or more insecure attachment at age 7. Insecure and disorganized attachment representations index risk of mental disorders and poorer functioning. Secure attachment may be a protective factor against mental disorders in children at FHR-SZ. Validation of the SSAP is needed.

Home environment of 11-year-old children born to parents with schizophrenia or bipolar disorder - a controlled, 4-year follow-up study: The Danish High Risk and Resilience Study - VIA 11.

BACKGROUND: The home environment has a major impact on child development. Parental severe mental illness can pose a challenge to the home environment of a child. We aimed to examine the home environment of children of parents with schizophrenia or bipolar disorder and controls longitudinally through at-home assessments. METHODS: Assessments were conducted within The Danish High Risk and Resilience Study, a nationwide multi-center cohort study of children of parents with schizophrenia or bipolar disorder and population-based controls. The level of at-home stimulation and support was measured at age 7 (N = 508 children) and age 11 (N = 430 children) with the semi-structured HOME Inventory. Results from the 11-year follow-up study were analyzed and compared with 7-year baseline results to examine change across groups. RESULTS: At age 11, children of parents with schizophrenia and bipolar disorder had lower levels of stimulation and support than controls (mean (s.d.) = 46.16 (5.56), 46.87 (5.34) and 49.25 (4.37) respectively, p < 0.001). A higher proportion of children with parental schizophrenia or bipolar disorder lived in inadequate home environments at age 11, compared with controls (N (%) = 24 (15.0), 12 (12.2) and 6 (3.5) respectively, p < 0.003). The changes in home environment scores did not differ across groups from age 7 to age 11. CONCLUSIONS: Assessed longitudinally from the children's age of 7 to 11, children of parents with schizophrenia or bipolar disorder had lower levels of stimulation and support in their homes than controls. Integrated support which can target practical, economic, social and health issues to improve the home environment is indicated.

A study of the genetic architecture of social responsiveness in families with parental schizophrenia or bipolar disorder and population-based controls.

Twin-studies of social responsiveness have reported moderate to high heritabilities, but studies using parent-child data are lacking. Additionally, social impairments have been suggested as a vulnerability marker for schizophrenia and bipolar disorder, but the heritability of social responsiveness in this context is unknown. This study is part of the Danish High Risk and Resilience Study - VIA, comprising families with one parent with schizophrenia (n = 202) or bipolar disorder (n = 120) and population-based controls (PBC, n = 200). Social responsiveness was assessed with The Social Responsiveness Scale, Second Edition (SRS-2). Heritability was estimated from variance components, and a polygenic risk score (PRS) for autism spectrum disorder (ASD) was calculated to assess the genetic relationship between ASD and SRS-2. SRS-2 heritability was moderate to high and significantly different from zero in all groups when the children were rated by the primary caregiver. With teacher ratings, the heritability was lower and only significant in the full cohort and PBC. We found no significant association between SRS-2 and PRS for ASD. Our study confirms that social responsiveness is heritable, but that heritability estimates are affected by the child-respondent relation and familial risk of mental illness. This has implications for clinical practice and research using SRS-2 and provides insight on the familial transmission of mental illness.

Suicidal Ideation and Non-Suicidal Self-Injury Following Early Childhood Psychotic Experiences in Preadolescent Children at Familial High Risk of Schizophrenia or Bipolar Disorder-The Danish High Risk and Resilience Study, VIA 11.

BACKGROUND AND HYPOTHESIS: Suicide is a leading cause of death in youth and is often preceded by suicidal ideation (SI) and non-suicidal self-injury (NSSI). Identifying early markers of risk for SI and NSSI could improve timely identification of at-risk individuals. STUDY DESIGN: Children (mean age 11.9, SD 0.2) at familial high risk of schizophrenia (N = 171), or bipolar disorder (N = 104), and controls (N = 174) were assessed for psychotic experiences (PE), SI, NSSI, and Axis I mental disorders in face-to-face interviews in early and middle childhood (age 7 and 11). STUDY RESULTS: Having 2 types of early childhood PE predicted middle childhood SI after accounting for previous SI, NSSI, and mental disorders (OR 2.8, 95% CI 1.1-6.9; P = .03). Two PE predicted NSSI (OR 3.0, 95% CI 1.2-7.7; P = .02) in excess of previous SI, NSSI, mental disorders, and familial risk. Persistent and incident PE predicted SI (OR 3.2, 95% CI, 1.1-8.8; P = .03; OR 3.8, 95% CI, 1.3-11.5; P = .02) in the fully adjusted model. Nineteen percent of children with persistent PE reported middle childhood SI vs 3.8% of those who never reported PE. In children with early childhood mental disorders, those who reported 2 PE had 4.4-fold increased odds of later SI (95% CI, 1.2-16.7; P = .03) after adjustments. PE were nondifferentially associated with outcomes across familial risk groups. CONCLUSIONS: Early childhood PE index elevated risk for subsequent SI and NSSI beyond what can be attributed to presence of mental disorders. Mental health screenings and clinical assessments should include early childhood PE.

Schizophrenia spectrum disorders in Denmark between 2000 and 2018: Incidence and early diagnostic transition.

BACKGROUND: Schizophrenia spectrum disorders (SSD) comprise a group of related mental disorders, which share clinical features and common genetic disposition, but it is unknown if there is a diagnostic transition between these disorders over time. We aimed to study the incidence at the first SSD diagnosis between 2000 and 2018, defined as schizophrenia, schizotypal or schizoaffective disorder, and the early diagnostic transition between these disorders. METHODS: Using Danish nationwide healthcare registers, we identified all individuals aged 15-64 years during the period from 2000 to 2018 in Denmark and calculated the yearly incidence rates for the specific SSDs. We studied the diagnostic pathways from the first ever diagnosis of an SSD across the subsequent two treatment courses with an SSD diagnosis to evaluate early diagnostic stability, and explore potential changes over time. RESULTS: Among 21,538 patients, yearly incidence rates per 10,000 individuals were similar during the observation period for schizophrenia (2000: 1.8; 2018: 1.6), lower for schizoaffective disorder (2000: 0.3; 2018: 0.1) and increasing for schizotypal disorder (2000: 0.7; 2018: 1.3). Among the subgroup of 13,417 individuals with three separate treatment courses, early diagnostic stability was present among 89.9% which differed between the disorders (schizophrenia: 95.4%; schizotypal disorder: 78.0%; schizoaffective disorder: 80.5%). Among 1352 (10.1%) experiencing an early diagnostic transition, 398 (3.0%) were diagnosed with schizotypal disorder after a schizophrenia or schizoaffective disorder diagnosis. CONCLUSION: This study provides comprehensive incidence rates for SSDs. The majority of patients experienced early diagnostic stability, but sizable proportions of people with initial schizophrenia or schizoaffective disorder are subsequently diagnosed with schizotypal disorder.