1. Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.
- Author
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Sønderby IE, Gústafsson Ó, Doan NT, Hibar DP, Martin-Brevet S, Abdellaoui A, Ames D, Amunts K, Andersson M, Armstrong NJ, Bernard M, Blackburn N, Blangero J, Boomsma DI, Bralten J, Brattbak HR, Brodaty H, Brouwer RM, Bülow R, Calhoun V, Caspers S, Cavalleri G, Chen CH, Cichon S, Ciufolini S, Corvin A, Crespo-Facorro B, Curran JE, Dale AM, Dalvie S, Dazzan P, de Geus EJC, de Zubicaray GI, de Zwarte SMC, Delanty N, den Braber A, Desrivières S, Donohoe G, Draganski B, Ehrlich S, Espeseth T, Fisher SE, Franke B, Frouin V, Fukunaga M, Gareau T, Glahn DC, Grabe H, Groenewold NA, Haavik J, Håberg A, Hashimoto R, Hehir-Kwa JY, Heinz A, Hillegers MHJ, Hoffmann P, Holleran L, Hottenga JJ, Hulshoff HE, Ikeda M, Jahanshad N, Jernigan T, Jockwitz C, Johansson S, Jonsdottir GA, Jönsson EG, Kahn R, Kaufmann T, Kelly S, Kikuchi M, Knowles EEM, Kolskår KK, Kwok JB, Hellard SL, Leu C, Liu J, Lundervold AJ, Lundervold A, Martin NG, Mather K, Mathias SR, McCormack M, McMahon KL, McRae A, Milaneschi Y, Moreau C, Morris D, Mothersill D, Mühleisen TW, Murray R, Nordvik JE, Nyberg L, Olde Loohuis LM, Ophoff R, Paus T, Pausova Z, Penninx B, Peralta JM, Pike B, Prieto C, Pudas S, Quinlan E, Quintana DS, Reinbold CS, Marques TR, Reymond A, Richard G, Rodriguez-Herreros B, Roiz-Santiañez R, Rokicki J, Rucker J, Sachdev P, Sanders AM, Sando SB, Schmaal L, Schofield PR, Schork AJ, Schumann G, Shin J, Shumskaya E, Sisodiya S, Steen VM, Stein DJ, Steinberg S, Strike L, Teumer A, Thalamuthu A, Tordesillas-Gutierrez D, Turner J, Ueland T, Uhlmann A, Ulfarsson MO, van 't Ent D, van der Meer D, van Haren NEM, Vaskinn A, Vassos E, Walters GB, Wang Y, Wen W, Whelan CD, Wittfeld K, Wright M, Yamamori H, Zayats T, Agartz I, Westlye LT, Jacquemont S, Djurovic S, Stefánsson H, Stefánsson K, Thompson P, and Andreassen OA
- Subjects
- Adult, Autism Spectrum Disorder genetics, Brain pathology, Chromosome Deletion, Chromosome Duplication, Chromosomes, Human, Pair 16 genetics, Databases, Factual, Female, Globus Pallidus pathology, Humans, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging methods, Male, Middle Aged, Neurodevelopmental Disorders genetics, Organ Size genetics, Putamen pathology, Schizophrenia genetics, Autistic Disorder genetics, Basal Ganglia pathology, Chromosome Disorders genetics, DNA Copy Number Variations genetics, Intellectual Disability genetics
- Abstract
Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10
-6 , 1.7 × 10- 9 , 3.5 × 10-12 and 1.0 × 10-4 , respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.- Published
- 2020
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