Polygenic risk of social isolation behavior and its influence on psychopathology and personality.

Social isolation has been linked to a range of psychiatric issues, but the behavioral component that drives it is not well understood. Here, a genome-wide associations study (GWAS) was carried out to identify genetic variants that contribute specifically to social isolation behavior (SIB) in up to 449,609 participants from the UK Biobank. 17 loci were identified at genome-wide significance, contributing to a 4% SNP-based heritability estimate. Using the SIB GWAS, polygenic risk scores (PRS) were derived in ALSPAC, an independent, developmental cohort, and used to test for association with self-reported friendship scores, comprising items related to friendship quality and quantity, at age 12 and 18 to determine whether genetic predisposition manifests during childhood development. At age 18, friendship scores were associated with the SIB PRS, demonstrating that the genetic factors can predict related social traits in late adolescence. Linkage disequilibrium (LD) score correlation using the SIB GWAS demonstrated genetic correlations with autism spectrum disorder (ASD), schizophrenia, major depressive disorder (MDD), educational attainment, extraversion, and loneliness. However, no evidence of causality was found using a conservative Mendelian randomization approach between SIB and any of the traits in either direction. Genomic Structural Equation Modeling (SEM) revealed a common factor contributing to SIB, neuroticism, loneliness, MDD, and ASD, weakly correlated with a second common factor that contributes to psychiatric and psychotic traits. Our results show that SIB contributes a small heritable component, which is associated genetically with other social traits such as friendship as well as psychiatric disorders.

Age-Related Social Cognitive Performance in Individuals With Psychotic Disorders and Their First-Degree Relatives.

BACKGROUND: Social cognitive impairment is a recognized feature of psychotic disorders. However, potential age-related differences in social cognitive impairment have rarely been studied. STUDY DESIGN: Data came from 905 individuals with a psychotic disorder, 966 unaffected siblings, and 544 never-psychotic controls aged 18-55 who participated in the Genetic Risk and Outcome of Psychosis (GROUP) study. Multilevel linear models were fitted to study group main effects and the interaction between group and age on emotion perception and processing (EPP; degraded facial affect recognition) and theory of mind (ToM; hinting task) performance. Age-related differences in the association between socio-demographic and clinical factors, and EPP and ToM were also explored. STUDY RESULTS: Across groups, EPP performance was associated with age (ß = -0.02, z = -7.60, 95% CI: -0.02, -0.01, P < .001), with older participants performing worse than younger ones. A significant group-by-age interaction on ToM (X2(2) = 13.15, P = .001) indicated that older patients performed better than younger ones, while no age-related difference in performance was apparent among siblings and controls. In patients, the association between negative symptoms and ToM was stronger for younger than older patients (z = 2.16, P = .03). CONCLUSIONS: The findings point to different age-related performance patterns on tests of 2 key social cognitive domains. ToM performance was better in older individuals, although this effect was only observed for patients. EPP was less accurate in older compared with younger individuals. These findings have implications with respect to when social cognitive training should be offered to patients.

Polygenic risk of Social-isolation and its influence on social behavior, psychosis, depression and autism spectrum disorder.

Social-isolation has been linked to a range of psychiatric issues, but the behavioral component that drives it is not well understood. Here, a GWAS is carried out to identify genetic variants which contribute to Social-isolation behaviors in up to 449,609 participants from the UK Biobank. 17 loci were identified at genome-wide significance, contributing to a 4% SNP heritability estimate. Using the Social-isolation GWAS, polygenic risk scores (PRS) were derived in ALSPAC, an independent, developmental cohort, and used to test for association with friendship quality. At age 18, friendship scores were associated with the Social-isolation PRS, demonstrating that the genetic factors are able to predict related social traits. LD score regression using the GWAS demonstrated genetic correlation with autism spectrum disorder, schizophrenia, and major depressive disorder. However, no evidence of causality was found using a conservative Mendelian randomization approach other than that of autism spectrum disorder on Social-isolation. Our results show that Social-isolation has a small heritable component which may drive those behaviors which is associated genetically with other social traits such as friendship satisfaction as well as psychiatric disorders.

Investigating the effects of genetic risk of schizophrenia on behavioural traits.

To characterise the trait-effects of increased genetic risk for schizophrenia, and highlight potential risk mediators, we test the association between schizophrenia polygenic risk scores (PRSs) and 529 behavioural traits (personality, psychological, lifestyle, nutritional) in the UK Biobank. Our primary analysis is performed on individuals aged 38-71 with no history of schizophrenia or related disorders, allowing us to report the effects of schizophrenia genetic risk in the sub-clinical general population. Higher schizophrenia PRSs were associated with a range of traits, including lower verbal-numerical reasoning (P = 6 × 10-61), higher nervous feelings (P = 1 × 10-46) and higher self-reported risk-taking (P = 3 × 10-38). We follow-up the risk-taking association, hypothesising that the association may be due to a genetic propensity for risk-taking leading to greater migration, urbanicity or drug-taking - reported environmental risk factors for schizophrenia, and all positively associated with risk-taking in these data. Next, to identify potential disorder or medication effects, we compare the PRS-trait associations in the general population to the trait values in 599 medicated and non-medicated individuals diagnosed with schizophrenia in the biobank. This analysis highlights, for example, levels of BMI, physical activity and risk-taking in cases in the opposite directions than expected from the PRS-trait associations in the general population. Our analyses offer simple yet potentially revealing insights into the possible causes of observed trait-disorder associations, which can complement approaches such as Mendelian Randomisation. While we urge caution in causal interpretations in PRS cross-trait studies that are highly powered to detect weak horizontal pleiotropy or population structure, we propose that well-designed polygenic score analyses have the potential to highlight modifiable risk factors that lie on the path between genetic risk and disorder.

Studying individual risk factors for self-harm in the UK Biobank: A polygenic scoring and Mendelian randomisation study.

BACKGROUND: Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm. METHODS AND FINDINGS: Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10-35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error. CONCLUSIONS: In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm.