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

Davies, Robert, International 22q11.2, Brain and Behavior Consortium, Fiksinski, Ania M., Breetvelt, Elemi J., Williams, Nigel M. ORCID:, Hooper, Stephen R., Monfueuga, Thomas, Bassett, Anne S., Owen, Michal J. ORCID:, Gur, Raquel E., Morrow, Bernice E., McDonald-McGinn, Donna M., Swillen, Ann, Chow, Eva W. C., van den Bree, Marianne ORCID:, Emanuel, Beverly S., Vermeesch, Joris R., van Amelsvoort, Therese, Arango, Celso, Armando, Marco, Campbell, Linda E., Cubells, Joseph F., Eliez, Stephan, Garia-Minaur, Sixto, Gothelf, Doron, Kates, Wendy R., Murphy, Kieran C., Murphy, Clodagh M., Murphy, Declan G., Philip, Nicole, Repetto, Gabriela M., Shashi, Vandana, Simon, Tony J., Suñer, Damiàn Heine., Vicari, Stefano, Scherer, Stephen W., Bearden, Carrie E., Vorstman, Jacob A. S. and Chawner, Samuel 2020. Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 Deletion Syndrome. Nature Medicine 26 , pp. 1912-1918. 10.1038/s41591-020-1103-1

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The 22q11.2 deletion syndrome (22q11DS) is associated with a 20 – 25% risk for schizophrenia.1,2 We examined phenotypic and genetic data in a cohort of 962 individuals with 22q11DS to evaluate the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: subthreshold symptoms of psychosis, low baseline intellectual functioning, and cognitive decline. We examined the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. These polygenic scores were not only associated with schizophrenia and baseline IQ, respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with subthreshold psychosis.Further, comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of 22q11DS subjects had schizophrenia, and 63% versus 24% had intellectual disability. Collectively, these data show both a shared genetic basis for schizophrenia and schizophrenia-related phenotypes, and highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Samuel Chawner is part of the International 22q11.2 Brain and Behavior Consortium
Publisher: Nature Publishing Group
ISSN: 1078-8956
Date of First Compliant Deposit: 3 August 2020
Date of Acceptance: 14 September 2020
Last Modified: 10 Nov 2023 17:19

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