Importance Schizophrenia is a highly heritable, polygenic condition characterized by a relatively diverse phenotype and frequent comorbid conditions, such as anxiety and depression. At present, limited evidence explains how genetic risk for schizophrenia is manifest in the general population. Objective To investigate the extent to which genetic risk for schizophrenia is associated with different phenotypes during adolescence in a population-based birth cohort. Design, Setting, and Participants This cohort study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Of 14 062 children in the birth cohort, genetic data were available for 9912 adolescents. Data were collected periodically from September 6, 1990, and collection is ongoing. Data were analyzed from March 4 to August 13, 2015. Exposures Polygenic risk scores (PRSs) for schizophrenia generated for individuals in the ALSPAC cohort using results of the second Psychiatric Genomics Consortium Schizophrenia genome-wide association study as a training set. Main Outcomes and Measures Logistic regression was used to assess associations between the schizophrenia PRS and (1) psychotic experiences (Psychosis-Like Symptom Interview at 12 and 18 years of age), (2) negative symptoms (Community Assessment of Psychic Experiences at 16.5 years of age), (3) depressive disorder (Development and Well-Being Assessment at 15.5 years of age), and (4) anxiety disorder (Development and Well-Being Assessment at 15.5 years of age) in adolescence. Results Of the 8230 ALSPAC participants whose genetic data passed quality control checks (51.2% male, 48.8% female), 3676 to 5444 participated in assessments from 12 to 18 years of age. The PRSs created using single-nucleotide polymorphisms with a training-set P ≤ .05 threshold were associated with negative symptoms (odds ratio [OR] per SD increase in PRS, 1.21; 95% CI, 1.08-1.36; R2 = 0.007) and anxiety disorder (OR per SD increase in PRS, 1.17; 95% CI, 1.06-1.29; R2 = 0.005). No evidence was found of an association between schizophrenia PRS and psychotic experiences (OR per SD increase in PRS, 1.08; 95% CI, 0.98-1.19; R2 = 0.001) or depressive disorder (OR per SD increase in PRS, 1.02; 95% CI, 0.91-1.13; R2 = 0.00005). Results were mostly consistent across different training-set P value thresholds and using different cutoffs and measures of the psychopathological outcomes. Conclusions and Relevance This study demonstrates polygenic overlaps between common genetic polymorphisms associated with schizophrenia and negative symptoms and anxiety disorder but not with psychotic experiences or depression. Because the genetic risk for schizophrenia appears to be manifest as anxiety and negative symptoms during adolescence, a greater focus on these phenotypes rather than on psychotic experiences might be required for prediction of transition in at-risk samples.

BackgroundRecent genome-wide association studies have identified genetic loci that jointly make a considerable contribution to risk of developing Alzheimer’s disease (AD). Because neuropathological features of AD can be present several decades before disease onset, we investigated whether effects of polygenic risk are detectable by neuroimaging in young adults. We hypothesized that higher polygenic risk scores (PRSs) for AD would be associated with reduced volume of the hippocampus and other limbic and paralimbic areas. We further hypothesized that AD PRSs would affect the microstructure of fiber tracts connecting the hippocampus with other brain areas.MethodsWe analyzed the association between AD PRSs and brain imaging parameters using T1-weighted structural (n = 272) and diffusion-weighted scans (n = 197).ResultsWe found a significant association between AD PRSs and left hippocampal volume, with higher risk associated with lower left hippocampal volume (p = .001). This effect remained when the APOE gene was excluded (p = .031), suggesting that the relationship between hippocampal volume and AD is the result of multiple genetic factors and not exclusively variability in the APOE gene. The diffusion tensor imaging analysis revealed that fractional anisotropy of the right cingulum was inversely correlated with AD PRSs (p = .009). We thus show that polygenic effects of AD risk variants on brain structure can already be detected in young adults.ConclusionsThis finding paves the way for further investigation of the effects of AD risk variants and may become useful for efforts to combine genotypic and phenotypic data for risk prediction and to enrich future prevention trials of AD.

Objective: To investigate the incidence, course and outcome of psychotic experiences from childhood through early adulthood in the general population, and prediction of psychotic disorder.Methods: A population-based cohort study using the semi-structured Psychosis-like Symptoms interview of psychotic experiences at ages 12, 18, and 24 (N=7900 with any data). Incidence rates were estimated using flexible parametric modelling, and positive predictive values (PPV), sensitivity, specificity, and area under the curve estimated for prediction. Results:The incidence rate of psychotic experiences increased between ages 13-24 years, peaking during late adolescence. Of 3866 interviewed at age 24, 313 (8.1%, 95%CI 7.2%, 9.0%) had a definite psychotic experience since age 12. 109 individuals (2.8%) met criteria for a psychotic disorder up to age 24, of whom 70% had sought professional help.Prediction of current psychotic disorder at age 24 (N=47, 1.2%) by both self-report and interviewerrated measures of psychotic experiences at age 18 (PPVs 2.9% and 10.0% respectively) was improved by incorporating information on frequency and distress (PPVs 13.3% and 20.0% respectively), although sensitivities were low. The PPV of an at-risk mental state at age 18 predicting incident disorder ages 18-24 was 21.1% (95%CI 6.1%-45.6%; sensitivity 14.3%, 95%CI 4.0%-32.7%). Conclusions:Our study shows a peak in incidence of psychotic experience during late adolescence, and an unmet need for care in young people with psychotic disorders. Because of the low sensitivity, targeting individuals in non-help-seeking samples based only on more severe symptom cut-off thresholds will likely have little impact on population-levels of first-episode psychosis.We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This publication is the work of all authors and SZ will serve as guarantor for the contents of this paper.

Whilst associations between polygenic risk scores (PRSs) for schizophrenia and various phenotypic outcomes have been reported, an understanding of developmental pathways can only be gained by modelling comorbidity across psychopathology. We examine how genetic risk for schizophrenia relates to adolescent psychosis-related and internalizing psychopathology using a latent modelling approach, and compare this to genetic risk for other psychiatric disorders, to gain a more comprehensive understanding of the developmental pathways at this age. PRSs for schizophrenia, major depressive disorder, neuroticism and bipolar disorder were generated for individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Multivariate linear regression was used to examine the relationships of these PRSs with psychopathology factors modelled within (i) a correlated factors structure and (ii) a bifactor structure. The schizophrenia PRS was associated with an increase in factors describing psychotic experiences, negative dimension, depression and anxiety, but, when modelling a general psychopathology factor based on these measures, specific effects above this persisted only for the negative dimension. Similar factor relationships were observed for the neuroticism PRS, with a (weak) specific effect only for anxiety once modelling general psychopathology. Psychopathology during adolescence can be described by a general psychopathology construct that captures common variance as well as by specific constructs capturing remaining non-shared variance. Schizophrenia risk genetic variants identified through genome-wide association studies mainly index negative rather than positive symptom psychopathology during adolescence. This has potentially important implications both for research and risk prediction in high-risk samples.