Louise K Hoeffding1, Betina B Trabjerg2, Line Olsen1, Wiktor Mazin1, Thomas Sparsø1, Anders Vangkilde1, Preben B Mortensen2, Carsten B Pedersen2, Thomas Werge3. 1. Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark2iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Lundbeck, Denmark. 2. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Lundbeck, Denmark3Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark4National Centre for Register-Based Research, Aarhus University, Business and Social Sciences, Aarhus, Denmark. 3. Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark2iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Lundbeck, Denmark5Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Abstract
Importance: Microdeletions and duplications have been described at the 22q11.2 locus. However, little is known about the clinical and epidemiologic consequences at the population level. Objective: To identify indicators of deletions or duplications at the 22q11.2 locus and estimate the incidence rate ratios (IRRs) and absolute risk for psychiatric disorders in clinically identified individuals with 22q11.2 deletion or duplication. Design, Setting, and Participants: A Danish nationwide register study including all individuals recorded in the Danish Cytogenetic Central Register with a 22q11.2 deletion or duplication was performed. A total of 3 768 943 individuals born in Denmark from 1955 to 2012 were followed up during the study period (total follow-up, 57.1 million person-years). Indicators of 22q11.2 deletion or duplication and cumulative incidences were estimated using a nested case-control design that included individuals from the population-based cohort. Survival analysis was used to compare risk of disease in individuals with and without the 22q11.2 deletion or duplication. The study was conducted from May 7, 2015, to August 14, 2016. Exposure: The 22q11.2 deletion or duplication. Main Outcomes and Measures: Indicators for carrying a 22q11.2 deletion or duplication, IRR, and cumulative incidences for psychiatric diagnoses (International Statistical Classification of Diseases and Related Health Problems, 10th Revision, codes F00-F99), including schizophrenia-spectrum disorders, mood disorders, neurotic stress-related and somatoform disorders, and a range of developmental and childhood disorders. Results: Among the 3 768 943 participants, 244 (124 [50.8%] male) and 58 (29 [50.0%] male) individuals were clinically identified with a 22q11.2 deletion or duplication, respectively. Mean (SD) age at diagnosis of any psychiatric disorder was 12.5 (8.3) years for individuals with deletions and 6.1 (0.9) years for duplication carriers. A parental diagnosis of schizophrenia-but not of other psychiatric diagnoses-was associated with a 22q11.2 deletion, and parental psychiatric diagnoses other than schizophrenia were associated with duplication carrier status. Both the 22q11.2 deletion (IRR, 4.24; 95% CI, 3.07-5.67) and duplication (IRR, 4.99; 95% CI, 1.79-10.72) was associated with increased risk of any psychiatric disorders. Furthermore, a highly increased risk of intellectual disability was found for the deletion (IRR, 34.08; 95% CI, 22.39-49.27) and duplication (IRR, 33.86; 95% CI, 8.42-87.87). Furthermore, individuals with the 22q11.2 deletion had an increased risk of several psychiatric disorders under study, for example, pervasive developmental disorders (IRR, 9.45; 95% CI, 5.64-14.69) and childhood autism (IRR, 8.94; 95% CI, 3.21-19.23). Conclusions and Relevance: Individuals with the 22q11.2 deletion or duplication have a significantly increased risk of developing psychiatric disorders. Survival analysis of persons carrying either the 22q11.2 deletion or duplication provides estimates of direct clinical relevance useful to assist clinical ascertainment, genetic counseling, guidance of symptomatic monitoring, and early clinical intervention.
Importance: Microdeletions and duplications have been described at the 22q11.2 locus. However, little is known about the clinical and epidemiologic consequences at the population level. Objective: To identify indicators of deletions or duplications at the 22q11.2 locus and estimate the incidence rate ratios (IRRs) and absolute risk for psychiatric disorders in clinically identified individuals with 22q11.2 deletion or duplication. Design, Setting, and Participants: A Danish nationwide register study including all individuals recorded in the Danish Cytogenetic Central Register with a 22q11.2 deletion or duplication was performed. A total of 3 768 943 individuals born in Denmark from 1955 to 2012 were followed up during the study period (total follow-up, 57.1 million person-years). Indicators of 22q11.2 deletion or duplication and cumulative incidences were estimated using a nested case-control design that included individuals from the population-based cohort. Survival analysis was used to compare risk of disease in individuals with and without the 22q11.2 deletion or duplication. The study was conducted from May 7, 2015, to August 14, 2016. Exposure: The 22q11.2 deletion or duplication. Main Outcomes and Measures: Indicators for carrying a 22q11.2 deletion or duplication, IRR, and cumulative incidences for psychiatric diagnoses (International Statistical Classification of Diseases and Related Health Problems, 10th Revision, codes F00-F99), including schizophrenia-spectrum disorders, mood disorders, neurotic stress-related and somatoform disorders, and a range of developmental and childhood disorders. Results: Among the 3 768 943 participants, 244 (124 [50.8%] male) and 58 (29 [50.0%] male) individuals were clinically identified with a 22q11.2 deletion or duplication, respectively. Mean (SD) age at diagnosis of any psychiatric disorder was 12.5 (8.3) years for individuals with deletions and 6.1 (0.9) years for duplication carriers. A parental diagnosis of schizophrenia-but not of other psychiatric diagnoses-was associated with a 22q11.2 deletion, and parental psychiatric diagnoses other than schizophrenia were associated with duplication carrier status. Both the 22q11.2 deletion (IRR, 4.24; 95% CI, 3.07-5.67) and duplication (IRR, 4.99; 95% CI, 1.79-10.72) was associated with increased risk of any psychiatric disorders. Furthermore, a highly increased risk of intellectual disability was found for the deletion (IRR, 34.08; 95% CI, 22.39-49.27) and duplication (IRR, 33.86; 95% CI, 8.42-87.87). Furthermore, individuals with the 22q11.2 deletion had an increased risk of several psychiatric disorders under study, for example, pervasive developmental disorders (IRR, 9.45; 95% CI, 5.64-14.69) and childhood autism (IRR, 8.94; 95% CI, 3.21-19.23). Conclusions and Relevance: Individuals with the 22q11.2 deletion or duplication have a significantly increased risk of developing psychiatric disorders. Survival analysis of persons carrying either the 22q11.2 deletion or duplication provides estimates of direct clinical relevance useful to assist clinical ascertainment, genetic counseling, guidance of symptomatic monitoring, and early clinical intervention.
Authors: Avanti Gokhale; Cortnie Hartwig; Amanda A H Freeman; Julia L Bassell; Stephanie A Zlatic; Christie Sapp Savas; Trishna Vadlamudi; Farida Abudulai; Tyler T Pham; Amanda Crocker; Erica Werner; Zhexing Wen; Gabriela M Repetto; Joseph A Gogos; Steven M Claypool; Jennifer K Forsyth; Carrie E Bearden; Jill Glausier; David A Lewis; Nicholas T Seyfried; Jennifer Q Kwong; Victor Faundez Journal: J Neurosci Date: 2019-03-04 Impact factor: 6.167
Authors: Ania M Fiksinski; Maude Schneider; Clodagh M Murphy; Marco Armando; Stefano Vicari; Jaume M Canyelles; Doron Gothelf; Stephan Eliez; Elemi J Breetvelt; Celso Arango; Jacob A S Vorstman Journal: Am J Med Genet A Date: 2018-09-08 Impact factor: 2.802