Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Davies RW

PROVIDER: S-EPMC7975627 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Davies Robert W RW Fiksinski Ania M AM Breetvelt Elemi J EJ Williams Nigel M NM Hooper Stephen R SR Monfeuga Thomas T Bassett Anne S AS Owen Michael J MJ Gur Raquel E RE Morrow Bernice E BE McDonald-McGinn Donna M DM Swillen Ann A Chow Eva W C EWC van den Bree Marianne M Emanuel Beverly S BS Vermeesch Joris R JR van Amelsvoort Therese T Arango Celso C Armando Marco M Campbell Linda E LE Cubells Joseph F JF Eliez Stephan S Garcia-Minaur Sixto S Gothelf Doron D Kates Wendy R WR Murphy Kieran C KC Murphy Clodagh M CM Murphy Declan G DG Philip Nicole N Repetto Gabriela M GM Shashi Vandana V Simon Tony J TJ Suñer Damiàn Heine DH Vicari Stefano S Scherer Stephen W SW Bearden Carrie E CE Vorstman Jacob A S JAS

Nature medicine 20201109 12

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 indivi ...[more]

PMID: 33169016

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Project description:22q11.2 deletion syndrome is characterised by a well defined microdeletion that is associated with a high risk of neuropsychiatric disorders, including intellectual disability, schizophrenia, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety disorders, seizures and epilepsy, and early-onset Parkinson's disease. Preclinical and clinical data reveal substantial variability of the neuropsychiatric phenotype despite the shared underlying deletion in this genetic model. Factors that might explain this variability include genetic background effects, additional rare pathogenic variants, and potential regulatory functions of some genes in the 22q11.2 deletion region. These factors might also be relevant to the pathophysiology of these neuropsychiatric disorders in the general population. We review studies that might provide insight into pathophysiological mechanisms underlying the expression of neuropsychiatric disorders in 22q11.2 deletion syndrome, and potential implications for these common disorders in the general (non-deleted) population. The recurrent hemizygous 22q11.2 deletion, associated with 22q11.2 deletion syndrome, has attracted attention as a genetic model for common neuropsychiatric disorders because of its association with substantially increased risk of such disorders.1 Studying such a model has many advantages. First, 22q11.2 deletion has been genetically well characterised.2 Second, most genes present in the region typically deleted at the 22q11.2 locus are expressed in the brain.3-5 Third, genetic diagnosis might be made early in life, long before recognisable neuropsychiatric disorders have emerged. Thus, this genetic condition offers a unique opportunity for early intervention, and monitoring individuals with 22q11.2 deletion syndrome throughout life could provide important information on factors contributing to disease risk and protection. Despite the commonly deleted region being shared by about 90% of individuals with 22q11.2 deletion syndrome, neuropsychiatric outcomes are highly variable between individuals and across the lifespan. A clear link remains to be established between genotype and phenotype.3,5 In this Review, we summarise preclinical and clinical studies investigating biological mechanisms in 22q11.2 deletion syndrome, with a focus on those that might provide insight into mechanisms underlying neuropsychiatric disorders in 22q11.2 deletion syndrome and in the general population.

Dataset Information

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

Publications

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

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