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

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journal contribution
posted on 2023-05-21, 00:12 authored by Sonderby, IE, Gustafsson, O, Doan, NT, Hibar, DP, Martin-Brevet, S, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Nicholas BlackburnNicholas Blackburn, Blangero, J, Boomsma, DI, Bralten, J, Brattbak, H-R, Brodaty, H, Brouwe, RM, Bulow, R, Calhoun, V, Caspers, S, Cavalleri, G, Chen, C-H, 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, Desrivieres, S, Donohoe, G, Draganski, B, Ehrlich, S, Espeseth, T, Fisher, SE, Franke, B, Frouin, V, Fukunaga, M, Hashimoto, R, Hehir-Kwa, JY, Heinz, A, Hillegers, MHJ, Hoffmann, P, Holleran, L, Hottenga, J-J, Hulshoff, HE, Ikeda, M, Jahanshad, N, Jernigan, T, Jockwitz, C, Johansson, S, Jonsdottir, GA, Jonsson, EG, Kahn, R, Kaufmann, T, Kelly, S, Kikuchi, M, Knowles, EEM, Kolskar, KK, Kwok, JB, Le Hellard, S, 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, Muhleisen, TW, Murray, R, Nordvik, JE, Nyberg, L, Loohuis, LMO, Ophoff, R, Paus, T, Pausova, Z, Penninx, B, Peralta, JM, Pike, B, Prieto, C, Pudas, S, Quinlan, E, Quintana, DS, Reinbold, CS, Reis Marques, T, Reymond, A, Richard, G, Rodriguez-Herreros, B, Roiz-Santianez, R, Rokicki, J, Rucker, J, Sachdev, P, Sanders, A-M, 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 En, 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, Stefansson, H, Stefansson, K, Thompson, P, Andreassen, OA
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.


Publication title

Molecular Psychiatry








Menzies Institute for Medical Research


Nature Publishing Group

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

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Diagnosis of human diseases and conditions; Expanding knowledge in the biological sciences

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