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 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 Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

2018 ◽  
Vol 49 (15) ◽  
pp. 2499-2504 ◽  
Author(s):  
Valentina Escott-Price ◽  
Daniel J. Smith ◽  
Kimberley Kendall ◽  
Joey Ward ◽  
George Kirov ◽  
...  
Keyword(s):  
Environmental Exposure ◽  
Copy Number Variants ◽  
Season Of Birth ◽  
Uk Biobank ◽  
Month Of Birth ◽  
Risk Alleles ◽  
Gene Environment ◽  
Increased Risk ◽  
The Uk ◽  
Pathogenic Process

AbstractBackgroundThere is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon.MethodsHere we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth.ResultsNeither genetic measure was associated with season or month of birth within the UKBB sample.ConclusionsAs our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure.

scholarly journals Neuropsychiatric copy number variants exert shared effects on human brain structure

2020 ◽  
Author(s):  
Claudia Modenato ◽  
Kuldeep Kumar ◽  
Clara Moreau ◽  
Sandra Martin-Brevet ◽  
Guillaume Huguet ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Brain Anatomy ◽  
Brain Volumes ◽  
Brain Morphometry ◽  
Main Gene ◽  
Psychiatric Conditions ◽  
Mirror Effects ◽  
The Uk ◽  
Meta Analyses

AbstractBackgroundCopy Number Variants (CNVs) associated with autism and schizophrenia have large effects on brain anatomy. Yet, neuroimaging studies have been conducted one mutation at a time. We hypothesize that neuropsychiatric CNVs may exert general effects on brain morphometry because they confer risk for overlapping psychiatric conditions.MethodsWe analyzed T1-weighted MRIs and characterized shared patterns on brain anatomy across 8 neuropsychiatric CNVs. Clinically ascertained samples included 1q21.1 (n=48), 16p11.2 (n=156), or 22q11.2 (n=96) and 331 non-carriers. Non-clinically ascertained samples from the UK Biobank included 1q21.1 (n=19), 16p11.2 (n=8), 22q11.2 (n=9), 15q11.2 (n=148) and 965 non-carriers. Canonical correlation analysis (CCA) and univariate models were used to interrogate brain morphometry changes across 8 CNVs.ResultsEight CNVs affect regional brain volumes along two main gene-morphometry dimensions identified by CCA. While fronto-temporal regions contributed to dimension 1, dimension 2 was driven by subcortical, parietal and occipital regions. Consistently, voxel-wise whole-brain analyses identified the same regions involved in patterns of alteration present across the 4 deletions and duplications. These neuroanatomical patterns are similar to those observed in cross-psychiatric disorder meta-analyses. Deletions and duplications at all 4 loci show mirror effects at either the global and/or the regional level.ConclusionNeuropsychiatric CNVs share neuroanatomical signatures characterized by a parsimonious set of brain dimensions. The latter may underlie the risk conferred by CNVs for a similar spectrum of neuropsychiatric conditions.

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 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.

The impact of copy number variants on brain anatomy

2019 ◽  
Vol 29 ◽  
pp. S441-S442
Author(s):  
C. Modenato ◽  
A. Pain ◽  
S. Martin-Brevet ◽  
A. Maillard ◽  
B. Rodriguez-Herreros ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Brain Anatomy ◽  
The Impact
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