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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Loes M. Olde Loohuis - , University of California at Los Angeles (Author)
  • Eva Mennigen - , Department of Psychiatry and Psychotherapy, University of California at Los Angeles, University Hospital Carl Gustav Carus Dresden (Author)
  • Anil P.S. Ori - , University of California at Los Angeles (Author)
  • Diana Perkins - , University of North Carolina at Chapel Hill (Author)
  • Elise Robinson - , Broad Institute of Harvard University and MIT, Harvard University (Author)
  • Jean Addington - , University of Calgary (Author)
  • Kristin S. Cadenhead - , University of California at San Diego (Author)
  • Barbara A. Cornblatt - , Zucker Hillside Hospital (Author)
  • Daniel H. Mathalon - , San Francisco Veterans Affairs Medical Center (SFVAMC) (Author)
  • Thomas H. McGlashan - , Yale University (Author)
  • Larry J. Seidman - , Harvard University (Author)
  • Matcheri S. Keshavan - , Harvard University (Author)
  • William S. Stone - , Harvard University (Author)
  • Ming T. Tsuang - , University of California at San Diego (Author)
  • Elaine F. Walker - , Emory University (Author)
  • Scott W. Woods - , Yale University (Author)
  • Tyrone D. Cannon - , Yale University (Author)
  • Ruben C. Gur - , University of Pennsylvania (Author)
  • Raquel E. Gur - , University of Pennsylvania (Author)
  • Carrie E. Bearden - , University of California at Los Angeles (Author)
  • Roel A. Ophoff - , University of California at Los Angeles, Erasmus University Rotterdam (Author)

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.

Details

Original languageEnglish
Article number80
JournalTranslational psychiatry
Volume11
Issue number1
Publication statusPublished - Jun 2021
Peer-reviewedYes

External IDs

PubMed 33510130
ORCID /0000-0001-5099-0274/work/157319095