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Review
. 2022 Jan;43(1):300-328.
doi: 10.1002/hbm.25354. Epub 2021 Feb 21.

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs

Ida E Sønderby  1   2   3 , Christopher R K Ching  4 , Sophia I Thomopoulos  4 , Dennis van der Meer  2   5 , Daqiang Sun  6   7 , Julio E Villalon-Reina  4 , Ingrid Agartz  8   9   10 , Katrin Amunts  11   12 , Celso Arango  13   14 , Nicola J Armstrong  15 , Rosa Ayesa-Arriola  14   16 , Geor Bakker  17   18 , Anne S Bassett  19   20   21 , Dorret I Boomsma  22   23 , Robin Bülow  24 , Nancy J Butcher  21   25 , Vince D Calhoun  26 , Svenja Caspers  11   27 , Eva W C Chow  19   21 , Sven Cichon  11   28   29 , Simone Ciufolini  30 , Michael C Craig  31 , Benedicto Crespo-Facorro  32 , Adam C Cunningham  33 , Anders M Dale  34   35 , Paola Dazzan  36 , Greig I de Zubicaray  37 , Srdjan Djurovic  1   38 , Joanne L Doherty  33   39 , Gary Donohoe  40 , Bogdan Draganski  41   42 , Courtney A Durdle  43 , Stefan Ehrlich  44 , Beverly S Emanuel  45 , Thomas Espeseth  46   47 , Simon E Fisher  48   49 , Tian Ge  50   51 , David C Glahn  52   53 , Hans J Grabe  54   55 , Raquel E Gur  56   57 , Boris A Gutman  58 , Jan Haavik  59   60 , Asta K Håberg  61   62 , Laura A Hansen  63 , Ryota Hashimoto  64   65 , Derrek P Hibar  66 , Avram J Holmes  67   68 , Jouke-Jan Hottenga  22 , Hilleke E Hulshoff Pol  69 , Maria Jalbrzikowski  70 , Emma E M Knowles  51   71 , Leila Kushan  72 , David E J Linden  73   74 , Jingyu Liu  26   75 , Astri J Lundervold  76 , Sandra Martin-Brevet  41 , Kenia Martínez  13   14   77 , Karen A Mather  78   79 , Samuel R Mathias  53   71 , Donna M McDonald-McGinn  45   80   81 , Allan F McRae  82 , Sarah E Medland  83 , Torgeir Moberget  84 , Claudia Modenato  41   85 , Jennifer Monereo Sánchez  73   86   87 , Clara A Moreau  88 , Thomas W Mühleisen  11   12   29 , Tomas Paus  89   90 , Zdenka Pausova  91 , Carlos Prieto  92 , Anjanibhargavi Ragothaman  93 , Céline S Reinbold  29   94 , Tiago Reis Marques  30   95 , Gabriela M Repetto  96 , Alexandre Reymond  97 , David R Roalf  56 , Borja Rodriguez-Herreros  98 , James J Rucker  36 , Perminder S Sachdev  78   99 , James E Schmitt  100 , Peter R Schofield  79   101 , Ana I Silva  74   102 , Hreinn Stefansson  103 , Dan J Stein  104 , Christian K Tamnes  2   9   105 , Diana Tordesillas-Gutiérrez  14   106 , Magnus O Ulfarsson  103   107 , Ariana Vajdi  72 , Dennis van 't Ent  22 , Marianne B M van den Bree  33 , Evangelos Vassos  108 , Javier Vázquez-Bourgon  14   16   109 , Fidel Vila-Rodriguez  110 , G Bragi Walters  103   111 , Wei Wen  78 , Lars T Westlye  3   46   112 , Katharina Wittfeld  54   55 , Elaine H Zackai  45   80 , Kári Stefánsson  103   111 , Sebastien Jacquemont  88   113 , Paul M Thompson  4 , Carrie E Bearden  6   114 , Ole A Andreassen  2 ; ENIGMA-CNV Working Group; ENIGMA 22q11.2 Deletion Syndrome Working Group
Collaborators, Affiliations
Review

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs

Ida E Sønderby et al. Hum Brain Mapp. 2022 Jan.

Abstract

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.

Keywords: brain structural imaging; copy number variant; diffusion tensor imaging; evolution; genetics-first approach; neurodevelopmental disorders; psychiatric disorders.

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Figures

FIGURE 1
FIGURE 1
Copy number variants. CNV carriers may have a deletion (one copy of region D, red) or duplication (three copies of region D, blue) compared with the normal copy number (two copies of region D, black). Reciprocal CNVs are a deletion and duplication occurring at the same locus
FIGURE 2
FIGURE 2
World map of the ENIGMA‐CNV and 22q‐ENIGMA WG study sites. A full list of participating cohorts and members for ENIGMA‐CNV and 22q‐ENIGMA may be found at the respective webpages: http://enigma.ini.usc.edu/ongoing/enigma‐cnv/enigma‐cnv‐co‐authors/ and http://enigma.ini.usc.edu/ongoing/enigma‐22q‐working‐group/22qwg/. Both working groups consist of international teams of clinicians, neuroscientists, engineers, bioinformaticians, statisticians, computer scientists, and geneticists who pool their resources to conduct large‐scale neuroimaging studies of CNVs
FIGURE 3
FIGURE 3
The overall procedure for participation in ENIGMA‐CNV and 22q‐ENIGMA
FIGURE 4
FIGURE 4
The subcortical findings from ENIGMA‐CNV, 22q‐ENIGMA and selected ENIGMA psychiatric working groups. Averaged left and right subcortical volume case versus non‐carriers (NC) Cohen's d effect size estimates for the ENIGMA SCZ (van Erp et al., 2016), ADHD (Hoogman et al., 2017), ASD (van Rooij et al., 2018), 22q11DS (Ching et al., 2020), 15q11.2 CNV (van der Meer, 2019), 16p11.2 distal CNV (Sønderby et al., 2018), and the 1q21.1 distal CNV (in review) studies. 22q+Psy vs. 22q‐Psy indicates a comparison from Ching et al. (2020) where a subset of individuals with 22q11.2 deletion syndrome with a history of psychosis were compared to a matched group of individuals with 22q11.2 deletion without a history of psychosis. Significant group differences are indicated by an asterisk (*); the plot includes vertical 95% confidence intervals
FIGURE 5
FIGURE 5
Cortical findings from the ENIGMA‐CNV, 22q‐ENIGMA, and selected ENIGMA psychiatric working groups. Copy number variant (CNV) analyses: for deletion or duplication carriers vs non‐carriers for the 15q11.2 CNVs (ICV‐corrected; van der Meer et al., 2019), 1q21.1 distal CNVs (ICV‐corrected; in review) and 22q11DS (Sun et al., 2018). 22q11DS results include 22q11DS psychosis deletion (Del+Psy) vs non psychosis deletion (Del‐Psy; left hemisphere shown). Behaviorally defined disorders analyses: Results are shown from case‐control studies from ASD's mega‐analysis (left hemisphere shown; van Rooij et al., 2018), all ages in ADHD combined (children, adolescents and adults; Hoogman et al., 2017), all types of epilepsies combined (left hemisphere shown; Whelan et al., 2018), and schizophrenia (SCZ; left hemisphere shown; van Erp et al., 2018). Only significant results are shown
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