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

International 22q11.2 Brain and Behavior Consortium, Rosemarie Fritsch

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


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.

Original languageEnglish
Pages (from-to)1912-1918
Number of pages7
JournalNature Medicine
Issue number12
StatePublished - Dec 2020

Bibliographical note

Funding Information:
This study was supported by the National Institute of Mental Health (NIMH) International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome (U01MH101719, U01MH0101720, U01MH0101723, U01MH101722 and EU01MH101724); the Lap-Chee Tsui Fellowship for Research Excellence and the CIHR STAGE Fellowship (to R.W.D.); the Brain and Behavior Research Foundation (to J.A.S.V.; Young Investigator Award); NIMH R01MH085953 and 1U01MH119736-01 (to C.E.B.); NIH RO1 MH064824 (to W.K.); Wellcome Trust grant 102428/Z/13/Z (to N.W. and T.M.); Canadian Institutes of Health Research grants MOP-79518, MOP-89066, MOP-97800 and MOP-111238, a McLaughlin Centre Accelerator grant, the Canada Research Chairs program and Dalglish Chair (to A.S.B); the Academic Scholars Award from the Department of Psychiatry, University of Toronto and the O’Brien Scholars Fund (to E.B.); Fondecyt 1171014 and ACT 192064 (ANID-Chile) (to G.R.); Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program (FP7-HEALTH-2013-2.2.1-2-603196 Project PSYSCAN) and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 115916, Project PRISM, and grant agreement 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz (to C.A); Innovative Medicines Initiative 2 Joint Undertaking (#777394 for the project AIMS-2-TRIALS), the NIHR Maudsley BRC (to D.M.); and Binational Science Foundation grant 2017369 (to R.E.G. and D.G.).

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.


  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • Cognitive Dysfunction
  • Cohort Studies
  • DiGeorge Syndrome
  • Female
  • Genetic Variation
  • Humans
  • Intellectual Disability
  • Male
  • Middle Aged
  • Multifactorial Inheritance
  • Phenotype
  • Risk Factors
  • Schizophrenia
  • Young Adult


Dive into the research topics of 'Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome'. Together they form a unique fingerprint.

Cite this