Phenotypic Manifestation of Genetic Risk for Schizophrenia During Adolescence in the General Population

Abstract

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.

30 Years on: How the Neurodevelopmental Hypothesis of Schizophrenia Morphed Into the Developmental Risk Factor Model of Psychosis

“…57 The PRS-SCZ accounts for about 9% of variance in caseness in studies of psychotic patients and controls. 59 Interestingly, it has been associated with neurodevelopmental problems and/or negative symptoms in several studies of non-ill children, 60 adolescents, 61 and adults. 62 In the huge UK Biobank sample, the PRS-SCZ predicts lower performance on a variety of cognitive tests.…”

Neuropsychology of the Social Brain Hypothesis of Schizophrenia: Symptoms, Personality and MRI Correlates

“…For example, Jones et al [43] recently noted that genetic risk for schizophrenia in adolescence is often expressed as anxiety and negative symptoms. These researchers called for a greater focus on these emotional processes rather than psychotic experiences as candidate disease endophenotypes.…”

Psychosis as a continuous phenotype in the general population: the thin line between normality and pathology

“…Indeed, individuals with common mental disorder are more likely to have psychotic experiences than their counterparts with no psychiatric disorder 4 , and such experiences in mood and anxiety disorders predict more severe illness course 4 .…”

“…Therefore, while van Os and Reininghaus argue that individuals in the community with psychotic experiences are more likely to develop a mood or anxiety disorder than a psychotic disorder, these phenomena actually predict psychotic disorders far more strongly 5 . This is because mood and anxiety disorders are much more common than psychotic disorders and frequently occur in the absence of psychotic experiences 4 . Consistent with this, as van Os and Reininghaus note, evidence from a Danish birth cohort study showed that psychotic experiences at age 11-12 years were strongly associated with a family history of psychotic disorder, but not of common mental disorder.…”

“…Eventually, these findings might feed into interventions targeting high-risk children. Similarly, Jones et al 4 have shown the importance of the transdiagnostic psychosis dimension in exploring how an increased genetic risk for schizophrenia expresses during early teens among the general public. Building on these findings, future studies may shed some light on the pathways between the genetic liability for schizophrenia and the phenotypical expression of this illness in childhood, adolescence and throughout adulthood.…”