Structural and functional brain alterations revealed by neuroimaging in CNV carriers
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 NeuroimagingGenetic Heterogeneity Shapes Brain Connectivity in Psychiatry
2023, Biological PsychiatryCitation 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).
Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes
2022, Biological PsychiatryCitation 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.