Stability of polygenic scores across discovery genome-wide association studies
Laura M. Schultz,
Alison K. Merikangas,
Kosha Ruparel,
Sébastien Jacquemont,
David C. Glahn,
Raquel E. Gur,
Ran Barzilay,
Laura Almasy
Affiliations
Laura M. Schultz
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Lifespan Brain Institute, Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Corresponding author
Alison K. Merikangas
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Lifespan Brain Institute, Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Kosha Ruparel
Lifespan Brain Institute, Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Sébastien Jacquemont
UHC Sainte-Justine Research Center, Université de Montréal, Montréal, QC H3T 1C5, Canada; Department of Pediatrics, Université de Montréal, Montréal, QC H3T 1C5, Canada
David C. Glahn
Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA
Raquel E. Gur
Lifespan Brain Institute, Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Child Adolescent Psychiatry and Behavioral Sciences, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Ran Barzilay
Lifespan Brain Institute, Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Child Adolescent Psychiatry and Behavioral Sciences, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Laura Almasy
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Lifespan Brain Institute, Children's Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Summary: Polygenic scores (PGS) are commonly evaluated in terms of their predictive accuracy at the population level by the proportion of phenotypic variance they explain. To be useful for precision medicine applications, they also need to be evaluated at the individual level when phenotypes are not necessarily already known. We investigated the stability of PGS in European American (EUR) and African American (AFR)-ancestry individuals from the Philadelphia Neurodevelopmental Cohort and the Adolescent Brain Cognitive Development study using different discovery genome-wide association study (GWAS) results for post-traumatic stress disorder (PTSD), type 2 diabetes (T2D), and height. We found that pairs of EUR-ancestry GWAS for the same trait had genetic correlations >0.92. However, PGS calculated from pairs of same-ancestry and different-ancestry GWAS had correlations that ranged from <0.01 to 0.74. PGS stability was greater for height than for PTSD or T2D. A series of height GWAS in the UK Biobank suggested that correlation between PGS is strongly dependent on the extent of sample overlap between the discovery GWAS. Focusing on the upper end of the PGS distribution, different discovery GWAS do not consistently identify the same individuals in the upper quantiles, with the best case being 60% of individuals above the 80th percentile of PGS overlapping from one height GWAS to another. The degree of overlap decreases sharply as higher quantiles, less heritable traits, and different-ancestry GWAS are considered. PGS computed from different discovery GWAS have only modest correlation at the individual level, underscoring the need to proceed cautiously with integrating PGS into precision medicine applications.
