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Martinez Rodriguez, KeniaAuthor

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

Publicated to:HUMAN BRAIN MAPPING. 43 (1): 300-328 - 2022-01-01 43(1), DOI: 10.1002/hbm.25354

Authors: Sønderby IE, Ching CRK, Thomopoulos SI, van der Meer D, Sun D, Villalon-Reina JE, Agartz I, Amunts K, Arango C, Armstrong NJ, Ayesa-Arriola R, Bakker G, Bassett AS, Boomsma DI, Bülow R, Butcher NJ, Calhoun VD, Caspers S, Chow EWC, Cichon S, Ciufolini S, Craig MC, Crespo-Facorro B, Cunningham AC, Dale AM, Dazzan P, de Zubicaray GI, Djurovic S, Doherty JL, Donohoe G, Draganski B, Durdle CA, Ehrlich S, Emanuel BS, Espeseth T, Fisher SE, Ge T, Glahn DC, Grabe HJ, Gur RE, Gutman BA, Haavik J, Håberg AK, Hansen LA, Hashimoto R, Hibar DP, Holmes AJ, Hottenga JJ, Hulshoff Pol HE, Jalbrzikowski M, Knowles EEM, Kushan L, Linden DEJ, Liu J, Lundervold AJ, Martin-Brevet S, Martínez K, Mather KA, Mathias SR, McDonald-McGinn DM, McRae AF, Medland SE, Moberget T, Modenato C, Monereo Sánchez J, Moreau CA, Mühleisen TW, Paus T, Pausova Z, Prieto C, Ragothaman A, Reinbold CS, Reis Marques T, Repetto GM, Reymond A, Roalf DR, Rodriguez-Herreros B, Rucker JJ, Sachdev PS, Schmitt JE, Schofield PR, Silva AI, Stefansson H, Stein DJ, Tamnes CK, Tordesillas-Gutiérrez D, Ulfarsson MO, Vajdi A, van 't Ent D, van den Bree MBM, Vassos E, Vázquez-Bourgon J, Vila-Rodriguez F, Walters GB, Wen W, Westlye LT, Wittfeld K, Zackai EH, Stefánsson K, Jacquemont S, Thompson PM, Bearden CE, Andreassen OA, ENIGMA-CNV Working Group, ENIGMA 22q11.2 Deletion Syndrome Working Group

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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.

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