Structural and functional brain alterations revealed by neuroimaging in CNV carriers

doi:10.1016/j.gde.2021.03.002

Current Opinion in Genetics & Development

Volume 68, June 2021, Pages 88-98

https://doi.org/10.1016/j.gde.2021.03.002 Get rights and content

Copy Number Variants (CNVs) are associated with elevated rates of neuropsychiatric disorders. A ‘genetics-first’ approach, involving the CNV effects on the brain, irrespective of clinical symptomatology, allows investigation of mechanisms underlying neuropsychiatric disorders in the general population. Recent years have seen an increasing number of larger multisite neuroimaging studies investigating the effect of CNVs on structural and functional brain endophenotypes. Alterations overlap with those found in idiopathic psychiatric conditions but effect sizes are twofold to fivefold larger. Here we review new CNV-associated structural and functional brain alterations and outline the future of neuroimaging genomics research, with particular emphasis on developing new resources for the study of high-risk CNVs and rare genomic variants.

Section snippets

Introduction: a brief history

Over the past two decades, the study of brain alterations associated with specific genetic conditions has offered a powerful tool for investigating gene–brain-behavior relationships in humans. Earlier structural and functional neuroimaging studies revealed insights into the impact of genetic conditions such as Fragile X [3], Turner Syndrome and Williams Syndrome on brain development and downstream behavior [4]. This ‘behavioral neurogenetics’ approach has shed light on potential mechanisms

Structural brain alterations in CNV carriers

Recent structural neuroimaging studies have included vastly larger samples of CNV carriers due to new efforts in data collection, development of international consortia, and, to some extent, large-scale population-based studies. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA), Variation in individual’s project (VIP) and European 16p11.2 Consortia have published multi-site studies of brain structure alterations in 22q11.2, 16p11.2 [10,11], and 15q11.2 CNVs [12^•], applying

Insights from the 22q11.2 microdeletion and Williams Syndrome

The 22q11.2 deletion syndrome (22q11DS; also known as Velocardiofacial Syndrome) has been more widely studied using neuroimaging techniques due to its relative frequency (at ∼1/4000 live births), large effects on neurodevelopment, and well-established link with schizophrenia. One in four individuals with 22q11DS develops psychotic illness, thus providing a powerful genetics-first framework to study brain markers for psychosis. A recent meta-analysis finds that 22q11DS is associated with

Gene dosage effects on the brain

Studies have revealed that reciprocal CNVs (i.e., deletions and duplications at the same locus) have opposing effects on brain phenotypes. Given the correlation between the number of genomic copies (deletions or duplications) and transcriptional levels of genes encompassed in CNVs [19], one may conclude that transcription levels quantitatively modulate structural and functional neuroimaging phenotypes. Intriguingly, the direction of such dosage effects differs across CNVs (Figure 2): while

Shared versus distinct neuroanatomic effects across CNVs

The polygenic nature of psychiatric conditions and the pleiotropic effects of genomic-risk variants could potentially be explained by the shared effects of genomic variants on brain alteration. The proportion of shared and specific effects associated with CNVs remains unknown. A recent examination of subcortical variation across CNVs found significantly smaller volumes (hippocampus, thalamus, putamen, pallidum, and accumbens) in 49 unaffected individuals carrying at least one of 12 CNVs known

Effects of CNVs versus effects of idiopathic Schizophrenia and ASD on brain structure

One of the key goals of neuroimaging studies of ‘neuropsychiatric’ CNVs is to determine whether there is convergence with underlying neuroanatomic alterations observed in complex polygenic idiopathic (i.e., behaviorally defined) developmental psychiatric disorders. To date, observations suggest that 1) CNVs with opposing effects on brain structure and function may be associated with the same neuropsychiatric condition; for example, 16p11.2 deletions and duplications are both associated with

Functional connectivity across CNVs

Functional connectivity (FC) studies have provided critical insight into the architecture of brain networks involved in neuropsychiatric disorders. FC represents the intrinsic low-frequency synchronization between different neuroanatomical regions. It is measured via resting-state functional magnetic resonance imaging (rs-fMRI) which captures fluctuations of blood oxygenation as an indirect measure of neural activity across brain areas when no explicit task is performed (Text Box 1). The field

Linking CNV-associated neuroimaging alterations to temporal and cytoarchitectural patterns of gene expression

Studies investigating the effects of CNVs on brain structure and function have provided a complex catalog of brain alteration patterns linked to different genomic loci. However, mechanisms linking CNVs to brain architecture remain largely unknown. Recent advances in large-scale, high-throughput transcriptomics, highlighted by the availability of brain-wide gene expression atlases such as the Allen Human Brain Atlas [43], have opened opportunities to study the relationship between temporal and

Datasets currently available for the analysis of CNVs

Studies on CNVs to date have been conducted either by recruiting clinically ascertained CNV carriers or by calling CNVs in unselected populations or (to a lesser extent) disease cohorts that were previously genotyped with the initial aim of conducting GWAS. While the latter strategy has enabled access to large sample sizes with a 0.5–3% rate of moderately to mildly deleterious CNVs, the former approach is the only way to obtain neuroimaging data in individuals with large and extreme effect-size

Developing new resources for the study of CNVs and rare genomic variants with large effect sizes

To increase our understanding of the effects of deleterious variants on brain architecture, efforts must be made to recruit individuals presenting with a broad spectrum of cognitive deficits and neuropsychiatric symptoms. Based on previous studies [52, 53, 54], this ascertainment strategy would provide a 10-fold to 30-fold enrichment in large effect size variants, including CNVs and single nucleotide variants. Further enrichment would also include individuals selected on the basis of having a

Conclusion

Identifying gene functions that may mediate the effect of CNVs on neuroimaging traits and risk for psychiatric conditions will require genome-wide analyses of a large number of genomic variants that alter genes with a broad variety of functions. Neuroimaging studies in animal models of CNVs are also beginning to shed light on the pathophysiology underlying brain alterations detected in human CNV carriers, although very few studies to date have directly compared neuroimaging findings between CNV

Funding

This work was supported by Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca), the Brain Canada Multi-Investigator initiative, the Canadian Institutes of Health Research, CIHR_400528, The Institute of Data Valorization (IVADO) through the Canada First Research Excellence Fund, Healthy Brains for Healthy Lives through the Canada First Research Excellence Fund, and the National Institute of Mental Health (grants R01MH085953, R21MH116473, and 9U01MH119736-02

Conflict of interest statement

Christopher Ching has received partial research support from Biogen, Inc. (Boston, USA) for work unrelated to the topic of this manuscript.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest

Acknowledgements

We wish to thank Sophia Thomopoulos for her assistance with accessing effect size data from the published ENIGMA studies for Figure 2. We also thank the ENIGMA 22q11.2 Deletion Syndrome Working Group (http://enigma.ini.usc.edu/ongoing/enigma-22q-working-group/) and CNV Working Group members (http://enigma.ini.usc.edu/ongoing/enigma-cnv/) for their contributions to these large-scale collaborative studies.

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Longitudinal Development of Thalamocortical Functional Connectivity in 22q11.2 Deletion Syndrome
2024, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
The 22q11.2 deletion syndrome (22qDel) is a genetic copy number variant that strongly increases risk for schizophrenia and other neurodevelopmental disorders. Disrupted functional connectivity between the thalamus and the somatomotor/frontoparietal cortex has been implicated in cross-sectional studies of 22qDel, idiopathic schizophrenia, and youths at clinical high risk for psychosis. Here, we used a novel functional atlas approach to investigate longitudinal age-related changes in network-specific thalamocortical functional connectivity (TCC) in participants with 22qDel and typically developing (TD) control participants.
TCC was calculated for 9 functional networks derived from resting-state functional magnetic resonance imaging scans collected from 65 participants with 22qDel (63.1% female) and 69 demographically matched TD control participants (49.3% female) ages 6 to 23 years. Analyses included 86 longitudinal follow-up scans. Nonlinear age trajectories were characterized with generalized additive mixed models.
In participants with 22qDel, TCC in the frontoparietal network increased until approximately age 13, while somatomotor TCC and cingulo-opercular TCC decreased from age 6 to 23. In contrast, no significant relationships between TCC and age were found in TD control participants. Somatomotor connectivity was significantly higher in participants with 22qDel than in TD control participants in childhood, but lower in late adolescence. Frontoparietal TCC showed the opposite pattern.
22qDel is associated with aberrant development of functional network connectivity between the thalamus and cortex. Younger individuals with 22qDel have lower frontoparietal connectivity and higher somatomotor connectivity than control individuals, but this phenotype may normalize or partially reverse by early adulthood. Altered maturation of this circuitry may underlie elevated neuropsychiatric disease risk in this syndrome.
Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers
2024, Biological Psychiatry
Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.
Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’s regional difference and global difference, were used to test for regional differences that diverge from the global difference.
For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.
We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
Genetic Heterogeneity Shapes Brain Connectivity in Psychiatry
2023, Biological Psychiatry
Citation Excerpt :
In line with this observation, PRS had minute effects on FC, and the latter was disproportionately low compared with that observed for CNVs with similar effect sizes on IQ and risk for autism or SZ. Effect sizes on FC across neurodevelopmental CNVs and psychiatric conditions are consistent with those reported for structural MRI measures (54,55) even when much larger samples are investigated (Cohen’s d = −1 and d = 0.6 for cortical surface and thickness, respectively, in n = 475 carriers of the 22q11.2 deletion) (56). For autism (57) and SZ (58), previously reported effect sizes for cortical thickness (Cohen’s d = 0.21 and 0.5, respectively) were also similar to those observed in our study for FC (54).
Polygenicity and genetic heterogeneity pose great challenges for studying psychiatric conditions. Genetically informed approaches have been implemented in neuroimaging studies to address this issue. However, the effects on functional connectivity of rare and common genetic risks for psychiatric disorders are largely unknown. Our objectives were to estimate and compare the effect sizes on brain connectivity of psychiatric genomic risk factors with various levels of complexity: oligogenic copy number variants (CNVs), multigenic CNVs, and polygenic risk scores (PRSs) as well as idiopathic psychiatric conditions and traits.
Resting-state functional magnetic resonance imaging data were processed using the same pipeline across 9 datasets. Twenty-nine connectome-wide association studies were performed to characterize the effects of 15 CNVs (1003 carriers), 7 PRSs, 4 idiopathic psychiatric conditions (1022 individuals with autism, schizophrenia, bipolar conditions, or attention-deficit/hyperactivity disorder), and 2 traits (31,424 unaffected control subjects).
Effect sizes on connectivity were largest for psychiatric CNVs (estimates: 0.2–0.65 z score), followed by psychiatric conditions (0.15–0.42), neuroticism and fluid intelligence (0.02–0.03), and PRSs (0.01–0.02). Effect sizes of CNVs on connectivity were correlated to their effects on cognition and risk for disease (r = 0.9, p = 5.93 × 10⁻⁶). However, effect sizes of CNVs adjusted for the number of genes significantly decreased from small oligogenic to large multigenic CNVs (r = −0.88, p = 8.78 × 10⁻⁶). PRSs had disproportionately low effect sizes on connectivity compared with CNVs conferring similar risk for disease.
Heterogeneity and polygenicity affect our ability to detect brain connectivity alterations underlying psychiatric manifestations.
Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes
2022, Biological Psychiatry
Citation Excerpt :
This leads us to our central question in this review: can such convergence across neurodevelopmental CNVs also be observed at the level of brain and cognition? Recent reviews have highlighted the importance of studying convergent brain (24) and cognitive (25) phenotypes in CNV carriers, while also noting that CNV-specific effects exist. In this review, we will describe emerging findings from cross-CNV studies on convergent cognitive and brain phenotypes and an overview of neuroimaging studies on individual CNV cohorts.
Genomic copy number variants (CNVs) are associated with a high risk of neurodevelopmental disorders. A growing body of genetic studies suggests that these high-risk genetic variants converge in common molecular pathways and that common pathways also exist across clinically distinct disorders, such as schizophrenia and autism spectrum disorder. A key question is how common molecular mechanisms converge into similar clinical outcomes. We review emerging evidence for convergent cognitive and brain phenotypes across distinct CNVs. Multiple CNVs were shown to have similar effects on core sensory, cognitive, and motor traits. Emerging data from multisite neuroimaging studies have provided valuable information on how these CNVs affect brain structure and function. However, most of these studies examined one CNV at a time, making it difficult to fully understand the proportion of shared brain effects. Recent studies have started to combine neuroimaging data from multiple CNV carriers and identified similar brain effects across CNVs. Some early findings also support convergence in CNV animal models. Systems biology, through integration of multilevel data, provides new insights into convergent molecular mechanisms across genetic risk variants (e.g., altered synaptic activity). However, the link between such key molecular mechanisms and convergent psychiatric phenotypes is still unknown. To better understand this link, we need new approaches that integrate human molecular data with neuroimaging, cognitive, and animal model data, while taking into account critical developmental time points. Identifying risk mechanisms across genetic loci can elucidate the pathophysiology of neurodevelopmental disorders and identify new therapeutic targets for cross-disorder applications.
Effects of gene dosage and development on subcortical nuclei volumes in individuals with 22q11.2 copy number variations
2024, Neuropsychopharmacology
Distinct neurocognitive profiles and clinical phenotypes associated with copy number variation at the 22q11.2 locus
2023, Autism Research

View all citing articles on Scopus

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Structural and functional brain alterations revealed by neuroimaging in CNV carriers

Section snippets

Introduction: a brief history

Structural brain alterations in CNV carriers

Insights from the 22q11.2 microdeletion and Williams Syndrome

Gene dosage effects on the brain

Shared versus distinct neuroanatomic effects across CNVs

Effects of CNVs versus effects of idiopathic Schizophrenia and ASD on brain structure

Functional connectivity across CNVs

Linking CNV-associated neuroimaging alterations to temporal and cytoarchitectural patterns of gene expression

Datasets currently available for the analysis of CNVs

Developing new resources for the study of CNVs and rare genomic variants with large effect sizes

Conclusion

Funding

Conflict of interest statement

References and recommended reading

Acknowledgements

Biol Psychiatry

Neuroscience

Neuroimage

Biol Psychiatry

J Neurosci

Cell

Circ Cardiovasc Genet

Neuroimage

Nat Neurosci

Am J Psychiatry

Mol Psychiatry

medRxiv

Brain-behavior participant similarity networks among youth and emerging adults with schizophrenia spectrum, autism spectrum, or bipolar disorder and matched controls

Neuropsychopharmacology

Brain imaging in neurogenetic conditions: realizing the potential of behavioral neurogenetics research

Ment Retard Dev Disabil Res Rev

Identification of common variants associated with human hippocampal and intracranial volumes

Nat Genet

ENIGMA and global neuroscience: a decade of large-scale studies of the brain in health and disease across more than 40 countries

Transl Psychiatry

Genome-wide association studies of brain imaging phenotypes in UK Biobank

Nature

The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions

Nat Commun

Dose response of the 16p.2 distal copy number variant on intracranial volume and basal ganglia

Mol Psychiatry

Association of copy number variation of the 15q.2 BP1-BP2 region with cortical and subcortical morphology and cognition

JAMA Psychiatry

Magnitude and heterogeneity of brain structural abnormalities in 22q11.2 deletion syndrome: a meta-analysis

Mol Psychiatry

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: convergence with idiopathic psychosis and effects of deletion size

Mol Psychiatry

Mapping subcortical brain alterations in 22q11.2 deletion syndrome: effects of deletion size and convergence with idiopathic neuropsychiatric illness

Am J Psychiatry

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study

Mol Psychiatry

Williams syndrome hemideletion and LIMK1 variation both affect dorsal stream functional connectivity

Brain

Williams syndrome neuroanatomical score associates with GTF2IRD1 in large-scale magnetic resonance imaging cohorts: a proof of concept for multivariate endophenotypes

Transl Psychiatry

Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p.2 locus

Nature

Developmental trajectories of neuroanatomical alterations associated with the 16p.2 copy number variations

Neuroimage

Globally divergent but locally convergent X- and Y-chromosome influences on cortical development

Cereb Cortex

Reciprocal white matter changes associated with copy number variation at 15q11.2 BP1-BP2: a diffusion tensor imaging study

Biol Psychiatry

CNVs conferring risk of autism or schizophrenia affect cognition in controls

Nature

Estimating the effect size of the 15Q.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice

J Med Genet

The genetic architecture of the human cerebral cortex

Science

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

Mol Psychiatry

Genetic risk for schizophrenia and developmental delay is associated with shape and microstructure of midline white-matter structures

Transl Psychiatry

Measuring and estimating the effect sizes of copy number variants on general intelligence in community-based samples

JAMA Psychiatry

Changes in cortical thickness during the course of illness in schizophrenia

Arch Gen Psychiatry

Cortical and subcortical brain morphometry differences between patients with autism spectrum disorder and healthy individuals across the lifespan: results from the ENIGMA ASD working group