Similar Rates of Deleterious Copy Number Variants in Early-Onset Psychosis and Autism Spectrum Disorder

Brownstein, Catherine A.; Douard, Élise; Mollon, Josephine; Smith, Richard; Hojlo, Margaret A.; Das, Ananth; Goldman, Maria Helena S.; Garvey, Emily; Cabral, Kristin; Li, Jianqiao; Bowen, Joshua; Rao, A. Venketeshwer; Genetti, Casie A.; Carroll, Devon; Knowles, Emma; Deaso, Emma; Agrawal, Pankaj B.; Beggs, Alan H.; D’Angelo, Eugene J.; Almasy, Laura; Alexander-Bloch, Aaron; Saci, Zohra; Moreau, Clara; Huguet, Guillaume; Deo, Anthony J.; Jacquemont, Sébastien; Glahn, David C.; Gonzalez–Heydrich, Joseph

doi:10.1176/appi.ajp.21111175

Cited by 14 publications

(10 citation statements)

References 40 publications

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“…While the ACMG scoring of these variants was unimpressive with only one reaching the criteria of VUS, this is to be expected for variants with low penetrance that influence the risk for common disease, as these guidelines were not developed for the interpretation of variants in genes associated with complex disorders. While we and others have identified Mendelian forms of EOP [ 7 , 13 , 24 ], it is clear that not all cases appear to be Mendelian in nature. It is possible that these variants are contributing to a background risk of neuropsychiatric disorders and additional genetic burden is necessary for the EOP phenotype to occur.…”

Section: Discussionmentioning

confidence: 58%

“…We recently documented that similarly to childhood-onset schizophrenia, children and adolescents with the broader EOP diagnosis have a two- to three-fold increase in recurrent CNVs relative to individuals with adult-onset schizophrenia [ 13 ]. This suggests that genetic burden, particularly for rare high penetrant mutations, is higher for individuals with EOP than it is for those with typical adult-onset psychotic spectrum disorders.…”

Section: Introductionmentioning

confidence: 99%

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Children with Early-Onset Psychosis Have Increased Burden of Rare GRIN2A Variants

Hojlo

Ghebrelul

Genetti

et al. 2023

Genes

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Background: Children and adolescents with early-onset psychosis (EOP) have more rare genetic variants than individuals with adult-onset forms of the illness, implying that fewer EOP participants are needed for genetic discovery. The Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) study predicted that 10 genes with ultra-rare variation were linked to adult-onset schizophrenia. We hypothesized that rare variants predicted “High” and “Moderate” by the Variant Effect Predictor Algorithm (abbreviated as VEPHMI) in these 10 genes would be enriched in our EOP cohort. Methods: We compared rare VEPHMI variants in individuals with EOP (N = 34) with race- and sex-matched controls (N = 34) using the sequence kernel association test (SKAT). Results: GRIN2A variants were significantly increased in the EOP cohort (p = 0.004), with seven individuals (20% of the EOP cohort) carrying a rare VEPHMI variant. The EOP cohort was then compared to three additional control cohorts. GRIN2A variants were significantly increased in the EOP cohort for two of the additional control sets (p = 0.02 and p = 0.02), and trending towards significance for the third (p = 0.06). Conclusion: Despite a small sample size, GRIN2A VEPHMI variant burden was increased in a cohort of individuals with EOP in comparison to controls. GRIN2A variants have been associated with a range of neuropsychiatric disorders including adult-onset psychotic spectrum disorder and childhood-onset schizophrenia. This study supports the role of GRIN2A in EOP and emphasizes its role in neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Children with Early-Onset Psychosis Have Increased Burden of Rare GRIN2A Variants

Hojlo

Ghebrelul

Genetti

et al. 2023

Genes

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“…In addition, genome-wide association studies (GWAS) also provided evidence that strengthens the hypothesis that common DNA variants contribute to the ASD phenotype, especially in cases that fall under the milder ends of the ASD spectrum [ 97 , 98 ].…”

Section: Discussionmentioning

confidence: 92%

The High Rates of Comorbidity among Neurodevelopmental Disorders: Reconsidering the Clinical Utility of Distinct Diagnostic Categories

Bonti,

Zerva,

Koundourou

et al. 2024

JPM

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The boundaries between neurodevelopmental disorders are often indistinct, even among specialists. But do these boundaries exist, or do experts struggle to distinguish and categorize symptoms in order to arrive at a dominant diagnosis while comorbidity continually leaves questions about where each disorder ends and begins? What should be reconsidered? The introduction of the term ‘spectrum of neurodevelopmental disorders’ could pave the way for a re-appraisal of the clinical continuum of neurodevelopmental disorders. This study aims to highlight the problems that emerge in the field of the differential diagnosis of neurodevelopmental disorders and propose a renegotiation of the distinctiveness criteria.

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“…The concept of the CNV risk score has emerged to estimate the tolerance to loss-of-function mutations and dosage sensitivity of genes by deletions or duplications 22 . CNV risk scores aim to measure the cumulative risk from deletions or duplications of large genomic segments.…”

Section: Introductionmentioning

confidence: 99%

The copy number variant architecture of psychopathology and cognitive development in the ABCD^®study

Sha,

Sun,

Jung

et al. 2024

Preprint

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Importance: Childhood is a crucial developmental phase for mental health and cognitive function, both of which are commonly affected in patients with psychiatric disorders. This neurodevelopmental trajectory is shaped by a complex interplay of genetic and environmental factors. While common genetic variants account for a large proportion of inherited genetic risk, rare genetic variations, particularly copy number variants (CNVs), play a significant role in the genetic architecture of neurodevelopmental disorders. Despite their importance, the relevance of CNVs to child psychopathology and cognitive function in the general population remains underexplored. Objective: Investigating CNV associations with dimensions of child psychopathology and cognitive functions. Design, Setting, and Participants: ABCD study focuses on a cohort of over 11,875 youth aged 9 to 10, recruited from 21 sites in the US, aiming to investigate the role of various factors, including brain, environment, and genetic factors, in the etiology of mental and physical health from middle childhood through early adulthood. Data analysis occurred from April 2023 to April 2024. Main Outcomes and Measures: In this study, we utilized PennCNV and QuantiSNP algorithms to identify duplications and deletions larger than 50Kb across a cohort of 11,088 individuals from the Adolescent Brain Cognitive Development study. CNVs meeting quality control standards were subjected to a genome-wide association scan to identify regions associated with quantitative measures of broad psychiatric symptom domains and cognitive outcomes. Additionally, a CNV risk score, reflecting the aggregated burden of genetic intolerance to inactivation and dosage sensitivity, was calculated to assess its impact on variability in overall and dimensional child psychiatric and cognitive phenotypes. Results: In a final sample of 8,564 individuals (mean age=9.9 years, 4,532 males) passing quality control, we identified 4,111 individuals carrying 5,760 autosomal CNVs. Our results revealed significant associations between specific CNVs and our phenotypes of interest, psychopathology and cognitive function. For instance, a duplication at 10q26.3 was associated with overall psychopathology, and somatic complaints in particular. Additionally, deletions at 1q12.1, along with duplications at 14q11.2 and 10q26.3, were linked to overall cognitive function, with particular contributions from fluid intelligence (14q11.2), working memory (10q26.3), and reading ability (14q11.2). Moreover, individuals carrying CNVs previously associated with neurodevelopmental disorders exhibited greater impairment in social functioning and cognitive performance across multiple domains, in particular working memory. Notably, a higher deletion CNV risk score was significantly correlated with increased overall psychopathology (especially in dimensions of social functioning, thought disorder, and attention) as well as cognitive impairment across various domains. Conclusions and Relevance: In summary, our findings shed light on the contributions of CNVs to interindividual variability in complex traits related to neurocognitive development and child psychopathology.

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Similar Rates of Deleterious Copy Number Variants in Early-Onset Psychosis and Autism Spectrum Disorder

Cited by 14 publications

References 40 publications

Children with Early-Onset Psychosis Have Increased Burden of Rare GRIN2A Variants

Children with Early-Onset Psychosis Have Increased Burden of Rare GRIN2A Variants

The High Rates of Comorbidity among Neurodevelopmental Disorders: Reconsidering the Clinical Utility of Distinct Diagnostic Categories

The copy number variant architecture of psychopathology and cognitive development in the ABCD^®study

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Similar Rates of Deleterious Copy Number Variants in Early-Onset Psychosis and Autism Spectrum Disorder

Cited by 14 publications

References 40 publications

Children with Early-Onset Psychosis Have Increased Burden of Rare GRIN2A Variants

Children with Early-Onset Psychosis Have Increased Burden of Rare GRIN2A Variants

The High Rates of Comorbidity among Neurodevelopmental Disorders: Reconsidering the Clinical Utility of Distinct Diagnostic Categories

The copy number variant architecture of psychopathology and cognitive development in the ABCD®study

Contact Info

Product

Resources

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The copy number variant architecture of psychopathology and cognitive development in the ABCD^®study