Specificity of Psychiatric Polygenic Risk Scores and Their Effects on Associated Risk Phenotypes

Amanda L Rodrigue; Samuel R Mathias; Emma E M Knowles; Josephine Mollon; Laura Almasy; Laura Schultz; Jessica Turner; Vince Calhoun; David C Glahn

doi:10.1016/j.bpsgos.2022.05.008

Specificity of Psychiatric Polygenic Risk Scores and Their Effects on Associated Risk Phenotypes

Biol Psychiatry Glob Open Sci. 2022 Jun 6;3(3):519-529. doi: 10.1016/j.bpsgos.2022.05.008. eCollection 2023 Jul.

Authors

Amanda L Rodrigue¹, Samuel R Mathias¹, Emma E M Knowles¹, Josephine Mollon¹, Laura Almasy^{2

3}, Laura Schultz^{2

3}, Jessica Turner^{4

5

6}, Vince Calhoun^{4

5

6

7

8}, David C Glahn^{1

9}

Affiliations

¹ Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
² Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
³ Penn-CHOP Lifespan Brain Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
⁴ Department of Psychology, Georgia State University, Georgia Institute of Technology, and Emory University, Atlanta, Georgia.
⁵ Neurosciences Institute, Georgia State University, Georgia Institute of Technology, and Emory University, Atlanta, Georgia.
⁶ Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, and Emory University, Atlanta, Georgia.
⁷ Departments of Neurosciences and Psychiatry and Behavioral Sciences, University of New Mexico School of Medicine, Albuquerque, New Mexico.
⁸ Mind Research Network, Departments of Psychiatry and Electrical and Computer Engineering, University of New Mexico, Albuquerque, New Mexico.
⁹ Olin Neuropsychiatry Research Center, Institute of Living, Hartford HealthCare, Hartford, Connecticut.

Abstract

Background: Polygenic risk scores (PRSs) are indices of genetic liability for illness, but their clinical utility for predicting risk for a specific psychiatric disorder is limited. Genetic overlap among disorders and their effects on allied phenotypes may be a possible explanation, but this has been difficult to quantify given focus on singular disorders and/or allied phenotypes.

Methods: We constructed PRSs for 5 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder) and 3 nonpsychiatric control traits (height, type II diabetes, irritable bowel disease) in the UK Biobank (N = 31,616) and quantified associations between PRSs and phenotypes allied with mental illness: behavioral (symptoms, cognition, trauma) and brain measures from magnetic resonance imaging. We then evaluated the extent of specificity among PRSs and their effects on these allied phenotypes.

Results: Correlations among psychiatric PRSs replicated previous work, with overlap between schizophrenia and bipolar disorder, which was distinct from overlap between autism spectrum disorder and attention-deficit/hyperactivity disorder; overlap between psychiatric and control PRSs was minimal. There was, however, substantial overlap of PRS effects on allied phenotypes among psychiatric disorders and among psychiatric disorders and control traits, where the extent and pattern of overlap was phenotype specific.

Conclusions: Results show that genetic distinctions between psychiatric disorders and between psychiatric disorders and control traits exist, but this does not extend to their effects on allied phenotypes. Although overlap can be informative, work is needed to construct PRSs that will function at the level of specificity needed for clinical application.

Keywords: Cognition; MRI; Polygenic risk score; Psychiatric genetics; Symptoms; Trauma.