Research Article: Genome‐wide analysis of adolescent psychotic‐like experiences shows genetic overlap with psychiatric disorders

Date Published: March 30, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Oliver Pain, Frank Dudbridge, Alastair G. Cardno, Daniel Freeman, Yi Lu, Sebastian Lundstrom, Paul Lichtenstein, Angelica Ronald.


This study aimed to test for overlap in genetic influences between psychotic‐like experience traits shown by adolescents in the community, and clinically‐recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic‐like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self‐ and parent‐ratings in three European community samples aged 15–19 years (Final N incl. siblings = 6,297–10,098). A mega‐genome‐wide association study (mega‐GWAS) for each psychotic‐like experience domain was performed. Single nucleotide polymorphism (SNP)‐heritability of each psychotic‐like experience domain was estimated using genomic‐relatedness‐based restricted maximum‐likelihood (GREML) and linkage disequilibrium‐ (LD‐) score regression. Genetic overlap between specific psychotic‐like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD‐score regression. GREML returned SNP‐heritability estimates of 3–9% for psychotic‐like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent‐rated Negative Symptoms). Mega‐GWAS analysis identified one genome‐wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic‐like experience trait domains (Paranoia and Hallucinations only in non‐zero scorers). The major depression PRS significantly predicted Anhedonia and Parent‐rated Negative Symptoms in adolescence. Psychotic‐like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically‐recognized psychiatric disorders, specifically schizophrenia and major depression.

Partial Text

Psychotic‐like experiences, also referred to as psychotic experiences, are traits in the community that at the extreme resemble symptoms of psychotic disorders, such as schizophrenia. Based on principal component analyses, psychotic‐like experiences can be separated into replicable and specific domains, such as positive, cognitive, and negative domains (Ronald et al., 2014; Wigman et al., 2012). Psychotic‐like experiences are common in the general population, particularly during adolescence (Freeman, 2006; Ronald et al., 2014). Evidence suggests that psychotic‐like experiences are dimensional: they show varying degrees of severity and taxometric analyses support their continuous nature in adolescence (Ahmed, Buckley, & Mabe, 2012; Daneluzzo et al., 2009; Taylor, Freeman, & Ronald, 2016). Adolescence is just prior to a peak time of onset for several psychiatric disorders, particularly schizophrenia, bipolar disorder, and major depression (Laursen, Munk‐Olsen, Nordentoft, & Mortensen, 2007). Psychotic‐like experiences predict many types of psychiatric disorders and suicidal ideation with significant odds ratios of 1.3–5.6 (Cederlöf et al., 2016; Fisher et al., 2013; Kelleher et al., 2014, 2012; McGrath et al., 2016; Werbeloff et al., 2012; Zammit et al., 2013).

Table 1 shows the descriptive statistics of psychotic‐like experience domains split by sample. The relationship between each psychotic‐like experience domain with age and sex are available in Supporting Information Tables S9 and S10. After phenotypic harmonization and quality control, the final sample sizes (including siblings) for all subsequent analyses were 8,665 for Paranoia and Hallucinations, 6,579 for Anhedonia, 6,297 for Cognitive Disorganization, and 10,098 for Parent‐rated Negative Symptoms.

A genetic relationship was identified between clinical schizophrenia and positive, cognitive, and negative psychotic‐like experience trait domains in adolescence. A higher genetic risk for schizophrenia significantly predicted adolescents having more cognitive disorganization, anhedonia, and parent‐rated negative symptoms, as well as more paranoia and hallucinations (this last finding was in the non‐zero scorers). Thus our findings suggest that psychotic‐like experience trait domains in adolescence comprise partly of the genetically‐influenced phenotypic manifestation of schizophrenia. Furthermore, higher genetic risk for major depression significantly predicted having more self‐rated anhedonia and parent‐rated negative symptoms as a teenager. Our results discredit the hypothesis that psychotic‐like experience trait domains in the general population are epiphenomena that do not share biological pathways with clinically‐recognized psychiatric disorders.

The authors declared that they have no conflict of interest.




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