Genetic and clinical analyses of psychosis spectrum symptoms in a large multiethnic youth cohort reveal significant link with ADHD

Loes Olde Loohuis ,Carrie E Bearden,Raquel E Gur,Thomas H Mcglashan,Matcheri S Keshavan,Scott W Woods,Elaine F Walker,Larry J Seidman,Eva Mennigen,Daniel H Mathalon,Diana O Perkins ,Kristin S Cadenhead,William S Stone,Tyrone D Cannon,Ruben C Gur,Anil P.s Ori ,Elise Robinson,Jean Addington,Barbara A Cornblatt,Ming T Tsuang,Roel A Ophoff

doi:10.1038/s41398-021-01203-2

Abstract

Psychotic symptoms are not only an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multiethnic sample of children and adolescents aged 8–22 years, the Philadelphia Neurodevelopmental Cohort (n = 7225, 20% PS). Using an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects. The multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is driven by subjects of European ancestry (OR = 1.23 (1.14, 1.34), P = 4.15 × 10−7) but is not observed in African American subjects (P = 0.65). We find a significant interaction of ADHD PGS with age (P = 0.01), with a stronger association in younger children. The association is independent of phenotypic overlap between ADHD and PS, not indirectly driven by substance use or childhood trauma, and appears to be specific to PS rather than reflecting general psychopathology in youth. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P = 0.02). Our findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories.

Highlights

Psychotic symptoms, such as delusions and hallucinations, are an important feature of severe psychiatric disorders such as schizophrenia and bipolar disorder
The landmark genome-wide association study (GWAS) of schizophrenia provides aggregate risk conferred by variants identified, polygenic scores (PGS), which explain about 7–10% of variance in case-control status[12,15]
In EA, the highest weight was consistently assigned to the PGS of attention deficit hyperactivity disorder (ADHD), with an average standardized coefficient of 0.09 corresponding to an odds ratio (OR) of 1.10 (Fig. 2), after correcting for all other selected variables

Summary

Introduction

Psychotic symptoms, such as delusions and hallucinations, are an important feature of severe psychiatric disorders such as schizophrenia and bipolar disorder. Youth experiencing psychotic symptoms typically exhibit a multitude of other comorbid symptoms, such as increased mood, anxiety, and attention deficit hyperactivity disorder (ADHD) symptoms, as well as increased. While subclinical psychopathology poses a risk for later development of overt psychiatric illnesses[5,8,9,10,11], only a minority of youth reporting psychotic symptoms will convert to full-blown psychotic disorders. With recent progress in psychiatric genetics, psychotic disorders are becoming well-characterized genetically[12,13,14]. In individuals with bipolar disorder, both genetic risk for schizophrenia as well as for bipolar disorder have been associated with psychotic symptoms[16,17]

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