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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia


Sonderby, IE and Gustafsson, O and Doan, NT and Hibar, DP and Martin-Brevet, S and Abdellaoui, A and Ames, D and Amunts, K and Andersson, M and Armstrong, NJ and Bernard, M and Blackburn, NB and Blangero, J and Boomsma, DI and Bralten, J and Brattbak, H-R and Brodaty, H and Brouwe, RM and Bulow, R and Calhoun, V and Caspers, S and Cavalleri, G and Chen, C-H and Cichon, S and Ciufolini, S and Corvin, A and Crespo-Facorro, B and Curran, JE and Dale, AM and Dalvie, S and Dazzan, P and de Geus, EJC and de Zubicaray, GI and de Zwarte, SMC and Delanty, N and den Braber, A and Desrivieres, S and Donohoe, G and Draganski, B and Ehrlich, S and Espeseth, T and Fisher, SE and Franke, B and Frouin, V and Fukunaga, M and Hashimoto, R and Hehir-Kwa, JY and Heinz, A and Hillegers, MHJ and Hoffmann, P and Holleran, L and Hottenga, J-J and Hulshoff, HE and Ikeda, M and Jahanshad, N and Jernigan, T and Jockwitz, C and Johansson, S and Jonsdottir, GA and Jonsson, EG and Kahn, R and Kaufmann, T and Kelly, S and Kikuchi, M and Knowles, EEM and Kolskar, KK and Kwok, JB and Le Hellard, S and Leu, C and Liu, J and Lundervold, AJ and Lundervold, A and Martin, NG and Mather, K and Mathias, SR and McCormack, M and McMahon, KL and McRae, A and Milaneschi, Y and Moreau, C and Morris, D and Mothersill, D and Muhleisen, TW and Murray, R and Nordvik, JE and Nyberg, L and Loohuis, LMO and Ophoff, R and Paus, T and Pausova, Z and Penninx, B and Peralta, JM and Pike, B and Prieto, C and Pudas, S and Quinlan, E and Quintana, DS and Reinbold, CS and Reis Marques, T and Reymond, A and Richard, G and Rodriguez-Herreros, B and Roiz-Santianez, R and Rokicki, J and Rucker, J and Sachdev, P and Sanders, A-M and Sando, SB and Schmaal, L and Schofield, PR and Schork, AJ and Schumann, G and Shin, J and Shumskaya, E and Sisodiya, S and Steen, VM and Stein, DJ and Steinberg, S and Strike, L and Teumer, A and Thalamuthu, A and Tordesillas-Gutierrez, D and Turner, J and Ueland, T and Uhlmann, A and Ulfarsson, MO and van 't En, D and van der Meer, D and van Haren, NEM and Vaskinn, A and Vassos, E and Walters, GB and Wang, Y and Wen, W and Whelan, CD and Wittfeld, K and Wright, M and Yamamori, H and Zayats, T and Agartz, I and Westlye, LT and Jacquemont, S and Djurovic, S and Stefansson, H and Stefansson, K and Thompson, P and Andreassen, OA, 16p11.2 European Consortium, for the ENIGMA-CNV working group, Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia, Molecular Psychiatry, 25, (3) pp. 584-602. ISSN 1359-4184 (2020) [Refereed Article]


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Copyright 2018 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0)

DOI: doi:10.1038/s41380-018-0118-1


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 noncarriers. 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.

Item Details

Item Type:Refereed Article
Keywords:brain morphology, copy number variations
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Neurogenetics
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biological sciences
UTAS Author:Blackburn, NB (Dr Nicholas Blackburn)
ID Code:144989
Year Published:2020
Web of Science® Times Cited:27
Deposited By:Menzies Institute for Medical Research
Deposited On:2021-06-23
Last Modified:2021-10-28
Downloads:6 View Download Statistics

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