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

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.

Download Full-text

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

10.31234/osf.io/tbjxh ◽

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.

Download Full-text

Brain structural differences between 73- and 92-year olds matched for childhood intelligence, social background, and intracranial volume

10.1101/135871 ◽

2017 ◽

Author(s):

Stuart J. Ritchie ◽

David Alexander Dickie ◽

Simon R. Cox ◽

Maria del C. Valdés Hernández ◽

Alison Pattie ◽

...

Keyword(s):

White Matter ◽

Cognitive Ability ◽

Surface Area ◽

Cortical Thickness ◽

White Matter Hyperintensity ◽

Socioeconomic Background ◽

Intracranial Volume ◽

Cortical Surface ◽

Age Cohorts ◽

Cortical Surface Area

AbstractFully characterizing age differences in the brain is a key task for combatting ageing-related cognitive decline. Using propensity score matching on two independent, narrow-age cohorts, we used data on childhood cognitive ability, socioeconomic background, and intracranial volume to match participants at mean age 92 years (n = 42) to very similar participants at mean age 73 (n = 126). Examining a variety of global and regional structural neuroimaging variables, there were large differences in grey and white matter volumes, cortical surface area, cortical thickness, and white matter hyperintensity volume and spatial extent. In a mediation analysis, the total volume of white matter hyperintensities and total cortical surface area jointly mediated 24.9% of the relation between age and general cognitive ability (tissue volumes and cortical thickness were not significant mediators in this analysis). These findings provide an unusual and valuable perspective on neurostructural ageing, in which brains from the eighth and tenth decades of life differ widely despite the same cognitive, socio-economic, and brain-volumetric starting points.

Download Full-text

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

The British Journal of Psychiatry ◽

10.1192/bjp.2018.301 ◽

2019 ◽

Vol 214 (5) ◽

pp. 297-304 ◽

Cited By ~ 22

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.

Download Full-text

Dosage Effects of BDNF Val66Met Polymorphism on Cortical Surface Area and Functional Connectivity

Journal of Neuroscience ◽

10.1523/jneurosci.3501-13.2014 ◽

2014 ◽

Vol 34 (7) ◽

pp. 2645-2651 ◽

Cited By ~ 28

Author(s):

C. Wang ◽

Y. Zhang ◽

B. Liu ◽

H. Long ◽

C. Yu ◽

...

Keyword(s):

Functional Connectivity ◽

Surface Area ◽

Cortical Surface ◽

Val66met Polymorphism ◽

Cortical Surface Area ◽

Dosage Effects ◽

Bdnf Val66met Polymorphism

Download Full-text

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.

Download Full-text

Cortical thickness, cortical surface area and subcortical volumes in schizophrenia and bipolar disorder patients with cannabis use

10.26226/morressier.5971be84d462b80290b52671 ◽

2017 ◽

Author(s):

Cecilie Bhandari Hartberg

Keyword(s):

Bipolar Disorder ◽

Surface Area ◽

Cortical Thickness ◽

Cannabis Use ◽

Cortical Surface ◽

Cortical Surface Area ◽

Subcortical Volumes

Download Full-text

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

Biological Psychiatry ◽

10.1016/j.biopsych.2021.02.969 ◽

2021 ◽

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 ◽

Copy Number ◽

Diffusion Tensor ◽

Uk Biobank ◽

Imaging Data ◽

Number Variation ◽

The Uk ◽

Diffusion Tensor Imaging Data

Download Full-text

The Concurrence of Cortical Surface Area Expansion and White Matter Myelination in Human Brain Development

Cerebral Cortex ◽

10.1093/cercor/bhy277 ◽

2018 ◽

Vol 29 (2) ◽

pp. 827-837 ◽

Cited By ~ 7

Author(s):

Riccardo Cafiero ◽

Jens Brauer ◽

Alfred Anwander ◽

Angela D Friederici

Keyword(s):

White Matter ◽

Human Brain ◽

Brain Development ◽

Surface Area ◽

Cortical Surface ◽

Cortical Surface Area ◽

Human Brain Development ◽

Area Expansion

Download Full-text

General Psychopathology, Cognition, and the Cerebral Cortex in 10-Year-Old Children: Insights From the Adolescent Brain Cognitive Development Study

Frontiers in Human Neuroscience ◽

10.3389/fnhum.2021.781554 ◽

2022 ◽

Vol 15 ◽

Author(s):

Yash Patel ◽

Nadine Parker ◽

Giovanni A. Salum ◽

Zdenka Pausova ◽

Tomáš Paus

Keyword(s):

Cerebral Cortex ◽

Cognitive Development ◽

Surface Area ◽

Cortical Surface ◽

Strongly Correlated ◽

General Psychopathology ◽

Cortical Surface Area ◽

Neurite Density ◽

The Relationship ◽

Strength Of Association

General psychopathology and cognition are likely to have a bidirectional influence on each other. Yet, the relationship between brain structure, psychopathology, and cognition remains unclear. This brief report investigates the association between structural properties of the cerebral cortex [surface area, cortical thickness, intracortical myelination indexed by the T1w/T2w ratio, and neurite density assessed by restriction spectrum imaging (RSI)] with general psychopathology and cognition in a sample of children from the Adolescent Brain Cognitive Development (ABCD) study. Higher levels of psychopathology and lower levels of cognitive ability were associated with a smaller cortical surface area. Inter-regionally—across the cerebral cortex—the strength of association between an area and psychopathology is strongly correlated with the strength of association between an area and cognition. Taken together, structural deviations particularly observed in the cortical surface area influence both psychopathology and cognition.

Download Full-text