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

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.

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The role of rare copy number variants in depression

10.1101/378307 ◽

2018 ◽

Cited By ~ 1

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.

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

Molecular Psychiatry ◽

10.1038/s41380-019-0355-y ◽

2019 ◽

Vol 25 (4) ◽

pp. 854-862 ◽

Cited By ~ 16

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

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

10.1101/374678 ◽

2018 ◽

Cited By ~ 1

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.

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

The British Journal of Psychiatry ◽

10.1192/bjp.2020.139 ◽

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.

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Analysis of diffusion tensor imaging data from UK Biobank confirms dosage effect of 15q11.2 copy-number variation on white matter and shows association with cognition

10.1101/2020.09.03.280859 ◽

2020 ◽

Author(s):

Ana I. Silva ◽

George Kirov ◽

Kimberley M. Kendall ◽

Mathew Bracher-Smith ◽

Lawrence S. Wilkinson ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Copy Number Variation ◽

Cognitive Performance ◽

Fractional Anisotropy ◽

Copy Number ◽

Diffusion Tensor ◽

Carrier Status ◽

Uk Biobank ◽

Number Variation

AbstractBackgroundCopy-number variations at the 15q11.2 BP1-BP2 locus are present in 0.5 to 1.0% of the population, and the deletion is associated with a range of neurodevelopmental disorders. Previously, we showed a reciprocal effect of 15q11.2 copy-number variation on fractional anisotropy, with widespread increases in deletion carriers. We aim to replicate and expand these findings, using a larger sample of participants (n=30,930), higher resolution imaging, and examining the implications for cognitive performance.MethodsDiffusion tensor imaging measures from participants with no neurological/psychiatric diagnoses were obtained from the UK Biobank database. We compared 15q11.2 BP1-BP2 deletion (n=103) and duplication (n=119) carriers to a large cohort of control individuals with no neuropsychiatric copy-number variants (n=29,870). Additionally, we assessed how changes in white matter mediated the association between carrier status and cognitive performance.ResultsDeletion carriers showed increases in fractional anisotropy in the internal capsule and cingulum, and decreases in the posterior thalamic radiation, compared to both duplication carriers and controls (who had intermediate values). Deletion carriers had lower scores across cognitive tasks compared to controls, which were mildly influenced by white matter alterations. Reduced fractional anisotropy in the posterior thalamic radiation partially contributed to worse cognitive performance in deletion carriers.ConclusionsThis study, together with our previous findings, provides convergent evidence for a dosage-dependent effect of 15q11.2 BP1-BP2 on white matter microstructure. Additionally, changes in white matter were found to partially mediate cognitive ability in deletion carriers, providing a link between white matter changes in 15q11.2 BP1-BP2 carriers and cognitive function.

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Large Copy-Number Variants in UK Biobank Caused by Clonal Hematopoiesis May Confound Penetrance Estimates

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2020.06.001 ◽

2020 ◽

Vol 107 (2) ◽

pp. 325-329

Author(s):

Marcus Tuke ◽

Jessica Tyrrell ◽

Katherine S. Ruth ◽

Robin N. Beaumont ◽

Andrew R. Wood ◽

...

Keyword(s):

Copy Number ◽

Copy Number Variants ◽

Uk Biobank ◽

Clonal Hematopoiesis

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Understanding Schizophrenia: Genetic Causes and Treatment

Current Neuropsychiatry and Clinical Neuroscience Reports ◽

10.33702/cncnr.2019.1.1.2 ◽

2019 ◽

Vol 1 (1) ◽

pp. 6-12

Author(s):

Fatima Javeria ◽

Shazma Altaf ◽

Alishah Zair ◽

Rana Khalid Iqbal

Keyword(s):

Copy Number ◽

Drug Targets ◽

Disease Risk ◽

Mental Disease ◽

Copy Number Variants ◽

Aminobutyric Acid ◽

Epigenetic Mechanisms ◽

Gamma Aminobutyric Acid ◽

Wide Range ◽

Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

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