Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

R.W. Davies, A.M. Fiksinski, E.J. Breetvelt, N.M. Williams, S.R. Hooper, T. Monfeuga, A.S. Bassett, M.J. Owen, R.E. Gur, B.E. Morrow, D.M. McDonald-McGinn, A. Swillen, E.W.C. Chow, M. van den Bree, B.S. Emanuel, J.R. Vermeesch, T. van Amelsvoort, C. Arango, M. Armando, L.E. CampbellJ.F. Cubells, S. Eliez, S. Garcia-Minaur, D. Gothelf, W.R. Kates, K.C. Murphy, C.M. Murphy, D.G. Murphy, N. Philip, G.M. Repetto, V. Shashi, T.J. Simon, D.H. Suner, S. Vicari, S.W. Scherer, C.E. Bearden, J.A.S. Vorstman*, International 22q11.2 Brain and Behavior Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.Polygenic risk scores are nearing a level of differentiation required for their clinical utility in risk prediction in populations with high-risk rare pathogenic genetic variants.
Original languageEnglish
Pages (from-to)1912-1918
Number of pages7
JournalNature Medicine
Issue number12
Publication statusPublished - 1 Dec 2020


  • abnormalities
  • cognitive-development
  • decline
  • intelligence
  • metaanalysis
  • performance
  • premorbid iq
  • psychosis
  • reliability
  • schizophrenia

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