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

• Type of Material: Article
• Authors: Loes M. Olde Loohuis, University of California Los Angeles; Eva Mennigen, University of California Los Angeles; Anil P. S. Ori, University of California Los Angeles; Diana Perkins, University of North Carolina; Elise Robinson, Broad Institute of MIT and Harvard; Jean Addington, Hotchkiss Brain Institute; Kristin S. Cadenhead, University of California San Diego; Barbara A. Cornblatt, Zucker Hillside Hospital; Daniel H. Mathalon, University of California San Francisco; Thomas H. McGlashan, Yale University; Larry J. Seidman, Harvard Medical School; Matcheri S. Keshavan, Harvard Medical School; William S. Stone, Harvard Medical School; Ming T. Tsuang, University of California San Diego; Elaine Walker, Emory University; Scott W. Woods, Yale University; Tyrone D. Cannon, Yale University; Ruben C. Gur, University of Pennsylvania; Raquel E. Gur, University of Pennsylvania; Carrie E. Bearden, University of California Los Angeles; Roel A. Ophoff, University of California Los Angeles
• Language: English
• Date: 2021-01-28
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41398-021-01203-2
• Title of Journal or Parent Work: TRANSLATIONAL PSYCHIATRY
• Volume: 11
• Issue: 1
• Start Page: 80
• End Page: 80
• Grant/Funding Information: This work was supported by R01MH107250 awarded to R.A.O. and C.E.B. L.O.L. was supported by K99/R00MH116115. Collaborative U01 award from the National Institute of Mental Health at the National Institutes of Health (MH081902 to T.D.C. and C.E.B.; MH081857 to B.A.C.; MH081988 to E.W.; MH081928 to L.S.; MH082004 to D.P.; MH081944 to K.C.; MH081984 to J.A.; MH082022 to S.W.W.; MH076989; MH107235 to R.C.G.; MH081902 to R.E.G.). We thank all research participants and researchers involved in making each GWAS summary statistic available and this work possible, including the 23andMe Inc. Research Team.
• Keywords: Psychiatry; Life Sciences & Biomedicine; Science & Technology
• Research Categories: Biology, Genetics; Psychology, Clinical; Psychology, Cognitive

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.