Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
Authors: Sønderby Ida E , Gústafsson Ómar , Doan Nhat Trung , Hibar Derrek P , Martin-Brevet Sandra , Abdellaoui Abdel , Ames David , Amunts Katrin , Andersson Michael , Armstrong Nicola J , Bernard Manon , Blackburn Nicholas , Blangero John , Boomsma Dorret I , Bralten Janita , Brattbak Hans-Richard , Brodaty Henry , Brouwer Rachel M , Bülow Robin , Calhoun Vince , Caspers Svenja , Cavalleri Gianpiero , Chen Chi-Hua , Cichon Sven , Ciufolini Simone , Corvin Aiden , Crespo-Facorro Benedicto , Curran Joanne E , Dale Anders M , Dalvie Shareefa , Dazzan Paola , de Geus Eco J C , de Zubicaray Greig I. , de Zwarte Sonja M. C. , Delanty Norman , den Braber Anouk , Desrivières Sylvane , Donohoe Gary , Draganski Bogdan , Ehrlich Stefan , Espeseth Thomas , Fisher Simon E , Franke Barbara , Frouin Vincent , Fukunaga Masaki , Gareau Thomas , Glahn David C , Grabe Hans , Groenewold Nynke A. , Haavik Jan , Håberg Asta , Hashimoto Ryota , Hehir-Kwa Jayne Y , Heinz Andreas , Hillegers Manon H. J. , Hoffmann Per , Holleran Laurena , Hottenga Jouke-Jan , Hulshoff Hilleke E , Ikeda Masashi , Jahanshad Neda , Jernigan Terry , Jockwitz Christiane , Johansson Stefan , Jonsdottir Gudrun A , Jönsson Erik G , Kahn Rene , Kaufmann Tobias , Kelly Sinead , Kikuchi Masataka , Knowles Emma E M , Kolskår Knut K , Kwok John B , Hellard Stephanie Le , Leu Costin , Liu Jingyu , Lundervold Astri J , Lundervold Arvid , Martin Nicholas G. , Mather Karen , Mathias Samuel R. , McCormack Mark , McMahon Katie L. , McRae Allan , Milaneschi Yuri , Moreau Clara , Morris Derek , Mothersill David , Mühleisen Thomas W , Murray Robin , Nordvik Jan E , Nyberg Lars , Olde Loohuis Loes M , Ophoff Roel , Paus Tomas , Pausova Zdenka , Penninx Brenda , Peralta Juan M , Pike Bruce , Prieto Carlos , Pudas Sara , Quinlan Erin , Quintana Daniel S , Reinbold Céline S , Marques Tiago Reis , Reymond Alexandre , Richard Genevieve , Rodriguez-Herreros Borja , Roiz-Santiañez Roberto , Rokicki Jarek , Rucker James , Sachdev Perminder , Sanders Anne-Marthe , Sando Sigrid B , Schmaal Lianne , Schofield Peter R , Schork Andrew J. , Schumann Gunter , Shin Jean , Shumskaya Elena , Sisodiya Sanjay , Steen Vidar M , Stein Dan J , Steinberg Stacy , Strike Lachlan , Teumer Alexander , Thalamuthu Anbu , Tordesillas-Gutierrez Diana , Turner Jessica , Ueland Torill , Uhlmann Anne , Ulfarsson Magnus O. , van ’t Ent Dennis , van der Meer Dennis , van Haren Neeltje E. M. , Vaskinn Anja , Vassos Evangelos , Walters G. Bragi , Wang Yunpeng , Wen Wei , Whelan Christopher D , Wittfeld Katharina , Wright Margie , Yamamori Hidenaga , Zayats Tetyana , Agartz Ingrid , Westlye Lars T , Jacquemont Sébastien , Djurovic Srdjan , Stefánsson Hreinn , Stefánsson Kári , Thompson Paul , Andreassen Ole A. ,   for the 16p11.2 European Consortium, for the ENIGMA-CNV working group
Published: October 2018

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.