scholarly journals Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank

2019 ◽  
Vol 214 (5) ◽  
pp. 297-304 ◽  
Author(s):  
Kimberley M. Kendall ◽  
Matthew Bracher-Smith ◽  
Harry Fitzpatrick ◽  
Amy Lynham ◽  
Elliott Rees ◽  
...  
Keyword(s):  
Cognitive Performance ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Cognitive Test ◽  
Carrier Status ◽  
Cognitive Tests ◽  
Uk Biobank ◽  
The Uk

BackgroundRare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.AimsWe aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.MethodWe called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.ResultsMost CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.ConclusionsCNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.Declaration of interestNone.

scholarly journals Effects of genomic copy number variants penetrant for schizophrenia on cortical thickness and surface area in healthy individuals: analysis of the UK Biobank

2020 ◽  
pp. 1-8
Author(s):  
Xavier Caseras ◽  
George Kirov ◽  
Kimberley M. Kendall ◽  
Elliott Rees ◽  
Sophie E. Legge ◽  
...  
Keyword(s):  
Surface Area ◽  
Cortical Thickness ◽  
Copy Number ◽  
Copy Number Variants ◽  
Brain Anatomy ◽  
Carrier Status ◽  
Uk Biobank ◽  
Risk Alleles ◽  
The Uk ◽  
The Impact

Background Schizophrenia is a highly heritable disorder with undetermined neurobiological causes. Understanding the impact on brain anatomy of carrying genetic risk for the disorder will contribute to uncovering its neurobiological underpinnings. Aims To examine the effect of rare copy number variants (CNVs) associated with schizophrenia on brain cortical anatomy in a sample of unaffected participants from the UK Biobank. Method We used regression analyses to compare cortical thickness and surface area (total and across gyri) between 120 unaffected carriers of rare CNVs associated with schizophrenia and 16 670 participants without any pathogenic CNV. A measure of cortical thickness and surface area covariance across gyri was also compared between groups. Results Carrier status was associated with reduced surface area (β = −0.020 mm2, P < 0.001) and less robustly with increased cortical thickness (β = 0.015 mm, P = 0.035), and with increased covariance in thickness (carriers z = 0.31 v. non-carriers z = 0.22, P < 0.0005). Associations were mainly present in frontal and parietal areas and driven by a limited number of rare risk alleles included in our analyses (mainly 15q11.2 deletion for surface area and 16p13.11 duplication for thickness covariance). Conclusions Results for surface area conformed with previous clinical findings, supporting surface area reductions as an indicator of genetic liability for schizophrenia. Results for cortical thickness, though, argued against its validity as a potential risk marker. Increased structural thickness covariance across gyri also appears related to risk for schizophrenia. The heterogeneity found across the effects of rare risk alleles suggests potential different neurobiological gateways into schizophrenia's phenotype.

scholarly journals Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Karen S. Ho ◽  
Hope Twede ◽  
Rena Vanzo ◽  
Erin Harward ◽  
Charles H. Hensel ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Detection Rate ◽  
Clinical Performance ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Ultrahigh Resolution ◽  
Significant Difference

Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic.

scholarly journals The role of rare copy number variants in depression

2018 ◽  
Author(s):  
Kimberley M Kendall ◽  
Elliott Rees ◽  
Matthew Bracher-Smith ◽  
Lucy Riglin ◽  
Stanley Zammit ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Genetic Risk ◽  
Copy Number ◽  
Social Deprivation ◽  
Copy Number Variants ◽  
Uk Biobank ◽  
Education Attainment ◽  
Increased Risk ◽  
Deletion 16P11.2

AbstractThe role of large, rare copy number variants (CNVs) in neurodevelopmental disorders is well-established,1–5 but their contribution to common psychiatric disorders, such as depression, remains unclear. We have previously shown that a substantial proportion of CNV enrichment in schizophrenia is explained by CNVs associated with neurodevelopmental disorders.6, 7 Depression shares genetic risk with schizophrenia8, 9 and is frequently comorbid with neurodevelopmental disorders10, 11, suggesting to us the hypothesis that if CNVs play a role in depression, neurodevelopmental CNVs are those most likely to be associated. We confirmed this in UK Biobank by showing that neurodevelopmental CNVs were associated with depression (24,575 cases, 5.87%; OR=1.36, 95% CI 1.22-1.51, p=1.61×10-8), whilst finding no evidence implicating other CNVs. Four individual neurodevelopmental CNVs increased risk of depression (1q21.1 duplication, PWS duplication, 16p13.11 deletion, 16p11.2 duplication). The association between neurodevelopmental CNVs and depression was partially explained by social deprivation but not by education attainment or physical illness.

scholarly journals 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

2021 ◽  
Author(s):  
Ida E. Sønderby ◽  
Dennis van der Meer ◽  
Clara Moreau ◽  
Tobias Kaufmann ◽  
G. Bragi Walters ◽  
...  
Keyword(s):  
Surface Area ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Dose Effect ◽  
Intracranial Volume ◽  
Cortical Surface ◽  
Uk Biobank ◽  
Cortical Surface Area ◽  
Dosage Effects ◽  
The Uk

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown.We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48 % male) derived from 15 distinct MRI scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers – the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

scholarly journals Schizophrenia-associated genomic copy number variants and subcortical brain volumes in the UK Biobank

2019 ◽  
Vol 25 (4) ◽  
pp. 854-862 ◽  
Author(s):  
Anthony Warland ◽  
Kimberley M. Kendall ◽  
Elliott Rees ◽  
George Kirov ◽  
Xavier Caseras
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Uk Biobank ◽  
Brain Volumes ◽  
Genomic Copy Number ◽  
Subcortical Brain ◽  
Genomic Copy ◽  
The Uk

scholarly journals Schizophrenia-associated genomic copy number variants and subcortical brain volumes in the UK Biobank

2018 ◽  
Author(s):  
Anthony Warland ◽  
Kimberley M Kendall ◽  
Elliott Rees ◽  
George Kirov ◽  
Xavier Caseras
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Risk Groups ◽  
Clinical Samples ◽  
Uk Biobank ◽  
Subcortical Structures ◽  
Brain Volumes ◽  
Subcortical Brain ◽  
Heritable Disorder ◽  
The Uk

AbstractSchizophrenia is a highly heritable disorder for which anatomical brain alterations have been repeatedly reported in clinical samples. Unaffected at-risk groups have also been studied in an attempt to identify brain changes that do not reflect reverse causation or treatment effects. However, no robust associations have been observed between neuroanatomical phenotypes and known genetic risk factors for schizophrenia. We tested subcortical brain volume differences between 49 unaffected participants carrying at least one of the 12 copy number variants associated with schizophrenia in UK Biobank and 9,063 individuals who did not carry any of the 93 copy number variants reported to be pathogenic. Our results show that CNV carriers have reduced volume in some of the subcortical structures previously shown to be reduced in schizophrenia. Moreover, these associations were partially accounted for by the association between pathogenic copy number variants and cognitive impairment, which is one of the features of schizophrenia.

scholarly journals Cognitive Performance Among Carriers of Pathogenic Copy Number Variants: Analysis of 152,000 UK Biobank Subjects

2017 ◽  
Vol 82 (2) ◽  
pp. 103-110 ◽  
Author(s):  
Kimberley M. Kendall ◽  
Elliott Rees ◽  
Valentina Escott-Price ◽  
Mark Einon ◽  
Rhys Thomas ◽  
...  
Keyword(s):  
Cognitive Performance ◽  
Copy Number ◽  
Copy Number Variants ◽  
Uk Biobank

scholarly journals The effect of schizophrenia-associated CNVs on other psychiatric disorders

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S248-S249
Author(s):  
Lily Farakish
Keyword(s):  
Psychiatric Disorders ◽  
Copy Number Variants ◽  
Clinical Importance ◽  
Carrier Status ◽  
Uk Biobank ◽  
Online Resource ◽  
Icd 10 ◽  
Heritable Disorder ◽  
Rare Genetic Variants ◽  
The Uk

AimsSchizophrenia is a highly heritable disorder, sharing genetic roots with other psychiatric disorders from both common and rare genetic variants. Copy number variants (CNVs) are one of the rare causes which increase the risk of a variety of psychiatric, medical and physical phenotypes. The role of schizophrenia-associated CNVs is becoming of increasingly scientific and clinical importance in the field of psychiatry, with new CNV-phenotype relationships opening perspectives for understanding the aetiology of psychiatric disorders. This paper aims to investigate whether 13 schizophrenia (SZ)-associated CNVs or any SZ-CNV-carrier status increase the risk for 9 psychiatric phenotypes, reduce levels of happiness, change duration of sleep, and increase the index of multiple deprivation.MethodThe study includes 421,268 participants of British or Irish descent (aged 40–69 years), containing 418,036 controls and 3232 schizophrenia-associated CNV carriers. The data are secondary from the UK Biobank, an online resource containing data on array-genotyped participants with their specific phenotypic information. Prior to analysis, CNV selection led to the exclusion of any CNV with less than 5 hits in the UK Biobank population. Incidence of each phenotype was based on self-reported diagnoses, questionnaires or hospital ICD-10 diagnoses, with a minimum of 500 cases. Both binary logistic and linear regression were used to assess the incidence of these phenotypes in relation to the CNVs, adjusted for age, sex, and ethnicity as potential cofounders.ResultOverall, 12/13 CNVs were nominally associated with at least one phenotype, including 114/168 possible associations and 54 undetectable associations as not every CNV carrier displayed one of the chosen phenotypes. 41 associations were statistically significant (p < 0.05) and 13 survived Bonferroni Correction (p < 2.98 × 10-4). All significant associations met the expected change except 15q11.2 deletion and any CNV carrier status which showed a decrease in likelihood of addiction.ConclusionThese findings suggest schizophrenia-associated CNV can affect range of psychiatric phenotypes. By building on existing reports, understanding the widespread effects of CNVs in the aetiology and pathogenicty of psychiatric disorders may overtime aid in strengthening our search for more targetted, effective treatments.Many thanks to Professor George Kirov for supervising and supporting this project.

scholarly journals 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ida E. Sønderby ◽  
◽  
Dennis van der Meer ◽  
Clara Moreau ◽  
Tobias Kaufmann ◽  
...  
Keyword(s):  
Surface Area ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Dose Effect ◽  
Intracranial Volume ◽  
Cortical Surface ◽  
Uk Biobank ◽  
Cortical Surface Area ◽  
Dosage Effects ◽  
The Uk

AbstractLow-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

scholarly journals Identifying schizophrenia patients who carry pathogenic genetic copy number variants using standard clinical assessment: retrospective cohort study

2020 ◽  
Vol 216 (5) ◽  
pp. 275-279 ◽  
Author(s):  
Claire Foley ◽  
Elizabeth A. Heron ◽  
Denise Harold ◽  
James Walters ◽  
Michael Owen ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Small Subset ◽  
Carrier Status ◽  
Discovery Cohort ◽  
Data Set ◽  
Phenotypic Features

BackgroundCopy number variants (CNVs) play a significant role in disease pathogenesis in a small subset of individuals with schizophrenia (~2.5%). Chromosomal microarray testing is a first-tier genetic test for many neurodevelopmental disorders. Similar testing could be useful in schizophrenia.AimsTo determine whether clinically identifiable phenotypic features could be used to successfully model schizophrenia-associated (SCZ-associated) CNV carrier status in a large schizophrenia cohort.MethodLogistic regression and receiver operating characteristic (ROC) curves tested the accuracy of readily identifiable phenotypic features in modelling SCZ-associated CNV status in a discovery data-set of 1215 individuals with psychosis. A replication analysis was undertaken in a second psychosis data-set (n = 479).ResultsIn the discovery cohort, specific learning disorder (OR = 8.12; 95% CI 1.16–34.88, P = 0.012), developmental delay (OR = 5.19; 95% CI 1.58–14.76, P = 0.003) and comorbid neurodevelopmental disorder (OR = 5.87; 95% CI 1.28–19.69, P = 0.009) were significant independent variables in modelling positive carrier status for a SCZ-associated CNV, with an area under the ROC (AUROC) of 74.2% (95% CI 61.9–86.4%). A model constructed from the discovery cohort including developmental delay and comorbid neurodevelopmental disorder variables resulted in an AUROC of 83% (95% CI 52.0–100.0%) for the replication cohort.ConclusionsThese findings suggest that careful clinical history taking to document specific neurodevelopmental features may be informative in screening for individuals with schizophrenia who are at higher risk of carrying known SCZ-associated CNVs. Identification of genomic disorders in these individuals is likely to have clinical benefits similar to those demonstrated for other neurodevelopmental disorders.

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