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Original Investigation |

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

Hannah J. Jones, PhD1,2; Evie Stergiakouli, PhD2; Katherine E. Tansey, PhD2; Leon Hubbard, PhD3; Jon Heron, PhD1; Mary Cannon, MD, PhD4; Peter Holmans, PhD3; Glyn Lewis, PhD5; David E. J. Linden, DPhil3; Peter B. Jones, PhD6; George Davey Smith, MD, DSc2; Michael C. O’Donovan, PhD, FRCPsych3; Michael J. Owen, PhD, FRCPsych3; James T. Walters, MRCPsych, PhD3; Stanley Zammit, MRCPsych, PhD1,3
[+] Author Affiliations
1Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, England
2Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, England
3MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, Wales
4Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin
5Division of Psychiatry, University College London, London, England
6Department of Psychiatry, University of Cambridge, Cambridge, England
JAMA Psychiatry. 2016;73(3):221-228. doi:10.1001/jamapsychiatry.2015.3058.
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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.

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Associations Between Polygenic Risk Scores (PRSs) for Schizophrenia and Phenotypes

Odds ratios (ORs) per SD change in PRS for schizophrenia are shown (data markers), with upper and lower error bars indicating 95% CIs. The ORs are shown for a range of PRSs generated using lists of single-nucleotide polymorphisms (SNPs) meeting a series of P value thresholds. The bars indicate the log10 times the number of SNPs used to create the PRSs. A genome-wide significant (threshold P = 5 × 10−8) PRS was created from 111 genome-wide significant schizophrenia SNPs as reported by the second Psychiatric Genomics Consortium.1 Red lines indicate the null value.

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