Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
Open accessAbstract
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.
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Human 16p11.2 deletion patients have larger volumes in these same structures.
“concordant with the increased volume of these structures in human deletion patients [54]”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [54]
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Microduplications of 16p11.2 are associated with schizophrenia
Wellcome Trust Case Control Consortium, McCarthy, S. E., Makarov, V., Kirov, G., Addington, A. M., McClellan, J., Yoon, S., Perkins, D. O., Dickel, D. E., Kusenda, M., et al. (2009) · Nature Genetics · doi:10.1038/ng.474 · Cited by 711 · see citing works
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A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders
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The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity
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Self-citationThe number of genomic copies at the 16p11.2 locus modulates language, verbal memory, and inhibition
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Self-citation15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia
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16p11.2 Copy Number Variations and Neurodevelopmental Disorders
Rein, B., & Yan, Z. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.09.001 · Cited by 160 · see citing works
Sønderby, I. E., Ching, C. R. K., Thomopoulos, S. I., van der Meer, D., Sun, D., Villalon‐Reina, J. E., Agartz, I., Amunts, K., Arango, C., Armstrong, N. J., et al. (2022) · Human Brain Mapping · doi:10.1002/hbm.25354 · Cited by 67 · see citing works
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- Authors
- Sønderby, I. E., Gústafsson, Ó., Doan, N. T., Hibar, D. P., Martin-Brevet, S., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N., Blangero, J., Boomsma, D. I., Bralten, J., Brattbak, H.-R., Brodaty, H., Brouwer, R. M., Bülow, R., Calhoun, V., Caspers, S., Cavalleri, G., Chen, C.-H., Cichon, S., Ciufolini, S., Corvin, A., Crespo-Facorro, B., Curran, J. E., Dale, A. M., Dalvie, S., Dazzan, P., de Geus, E. J. C., de Zubicaray, G. I., de Zwarte, S. M. C., Delanty, N., den Braber, A., Desrivières, S., Donohoe, G., Draganski, B., Ehrlich, S., Espeseth, T., Fisher, S. E., Franke, B., Frouin, V., Fukunaga, M., Gareau, T., Glahn, D. C., Grabe, H., Groenewold, N. A., Haavik, J., Håberg, A., Hashimoto, R., Hehir-Kwa, J. Y., Heinz, A., Hillegers, M. H. J., Hoffmann, P., Holleran, L., Hottenga, J.-J., Hulshoff, H. E., Ikeda, M., Jahanshad, N., Jernigan, T., Jockwitz, C., Johansson, S., Jonsdottir, G. A., Jönsson, E. G., Kahn, R., Kaufmann, T., Kelly, S., Kikuchi, M., Knowles, E. E. M., Kolskår, K. K., Kwok, J. B., Hellard, S. L., Leu, C., Liu, J., Lundervold, A. J., Lundervold, A., Martin, N. G., Mather, K., Mathias, S. R., McCormack, M., McMahon, K. L., McRae, A., Milaneschi, Y., Moreau, C., Morris, D., Mothersill, D., Mühleisen, T. W., Murray, R., Nordvik, J. E., Nyberg, L., Olde Loohuis, L. M., Ophoff, R., Paus, T., Pausova, Z., Penninx, B., Peralta, J. M., Pike, B., Prieto, C., Pudas, S., Quinlan, E., Quintana, D. S., Reinbold, C. S., Marques, T. R., Reymond, A., Richard, G., Rodriguez-Herreros, B., Roiz-Santiañez, R., Rokicki, J., Rucker, J., Sachdev, P., Sanders, A.-M., Sando, S. B., Schmaal, L., Schofield, P. R., Schork, A. J., Schumann, G., Shin, J., Shumskaya, E., Sisodiya, S., Steen, V. M., Stein, D. J., Steinberg, S., Strike, L., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J., Ueland, T., Uhlmann, A., Ulfarsson, M. O., van ’t Ent, D., van der Meer, D., van Haren, N. E. M., Vaskinn, A., Vassos, E., Walters, G. B., Wang, Y., Wen, W., Whelan, C. D., Wittfeld, K., Wright, M., Yamamori, H., Zayats, T., Agartz, I., Westlye, L. T., Jacquemont, S., Djurovic, S., Stefánsson, H., Stefánsson, K., Thompson, P., Andreassen, O. A., & for the 16p11.2 European Consortium, F. T. E.-C. W. G.
- Affiliations
- Oslo University Hospital (NO)
- deCODE Genetics (Iceland) (IS)
- University of Southern California (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- The University of Melbourne (AU)
- Forschungszentrum Jülich (DE)
- Umeå University (SE)
- Murdoch University (AU)
- University of Toronto (CA)
- The University of Texas Rio Grande Valley (US)
- Vrije Universiteit Amsterdam (NL)
- Radboud University Medical Center (NL)
- Haukeland University Hospital (NO)
- UNSW Sydney (AU)
- University Medical Center Utrecht (NL)
- Universitätsmedizin Greifswald (DE)
- Mind Research Network (US)
- Royal College of Surgeons in Ireland (IE)
- University of California San Diego (US)
- King's College London (GB)
- Trinity College Dublin (IE)
- Ollscoil na Gaillimhe – University of Galway (IE)
- Centre Hospitalier Universitaire Vaudois (CH)
- Massachusetts General Hospital (US)
- Radboud University Nijmegen (NL)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- National Institute for Physiological Sciences (JP)
- Hartford Hospital (US)
- University of Bergen (NO)
- Molecular Research Center for Children's Mental Development (JP)
- Humboldt-Universität zu Berlin (DE)
- Erasmus MC (NL)
- University of Bonn (DE)
- Fujita Health University (JP)
- The University of Osaka (JP)
- Yale University (US)
- The University of Sydney (AU)
- Cleveland Clinic (US)
- QIMR Berghofer Medical Research Institute (AU)
- The University of Queensland (AU)
- Amsterdam Neuroscience (NL)
- CHU Sainte-Justine Research Center (CA)
- Sunnaas sykehus (NO)
- University of California, Los Angeles (US)
- Universidad de Salamanca (ES)
- University of Basel (CH)
- University of Lausanne (CH)
- Norwegian University of Science and Technology (NO)
- UCL Queen Square Institute of Neurology (GB)
- University of Cape Town (ZA)
- Georgia State University (US)
- Stellenbosch University (ZA)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Andreassen, Ole A.
- ORCID
- Sønderby, Ida E
- Doan, Nhat Trung
- Abdellaoui, Abdel
- Amunts, Katrin
- Armstrong, Nicola J
- Bernard, Manon
- Blackburn, Nicholas
- Blangero, John
- Boomsma, Dorret I
- Bralten, Janita
- Brodaty, Henry
- Brouwer, Rachel M
- Bülow, Robin
- Calhoun, Vince
- Caspers, Svenja
- Cavalleri, Gianpiero
- Chen, Chi-Hua
- Cichon, Sven
- Ciufolini, Simone
- Corvin, Aiden
- Curran, Joanne E
- Dale, Anders M
- Dalvie, Shareefa
- Dazzan, Paola
- Delanty, Norman
- 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
- Hashimoto, Ryota
- Heinz, Andreas
- Hillegers, Manon H. J.
- Hoffmann, Per
- Holleran, Laurena
- Hottenga, Jouke-Jan
- Ikeda, Masashi
- Jahanshad, Neda
- Jernigan, Terry
- Jockwitz, Christiane
- Johansson, Stefan
- Jönsson, Erik G
- Kaufmann, Tobias
- Kikuchi, Masataka
- Kolskår, Knut K
- Kwok, John B
- 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
- Ophoff, Roel
- Penninx, Brenda
- Peralta, Juan M
- Prieto, Carlos
- Pudas, Sara
- Quinlan, Erin
- Quintana, Daniel S
- Reinbold, Céline S
- Marques, Tiago Reis
- Reymond, Alexandre
- Rucker, James
- Sachdev, Perminder
- Sanders, Anne-Marthe
- Sando, Sigrid B
- Schmaal, Lianne
- Schofield, Peter R
- Schork, Andrew J.
- Shin, Jean
- Shumskaya, Elena
- Sisodiya, Sanjay
- Stein, Dan J
- Steinberg, Stacy
- Strike, Lachlan
- Teumer, Alexander
- Turner, Jessica
- Ueland, Torill
- Uhlmann, Anne
- Ulfarsson, Magnus O.
- Vaskinn, Anja
- Vassos, Evangelos
- Walters, G. Bragi
- Wang, Yunpeng
- Wen, Wei
- Whelan, Christopher D
- Wittfeld, Katharina
- Yamamori, Hidenaga
- Zayats, Tetyana
- Agartz, Ingrid
- Westlye, Lars T
- Jacquemont, Sébastien
- Djurovic, Srdjan
- Stefánsson, Hreinn
- Thompson, Paul
- Andreassen, Ole A.
- Venue
- Molecular Psychiatry
- Published
- 2018-10-03
- Volume
- 25
- Issue
- 3
- Pages
- 584-602
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC7042770
- OpenAlex
- W2894642038
- Cited by
- 66
- References
- 8
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 11 · 2023: 8 · 2022: 8 · 2021: 11 · 2020: 13 · 2019: 6
- FWCI
- 4.59
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-01-31)
- Open access
- hybrid
- doi.org
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- Molecular Psychiatry (publishedVersion, cc-by)
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- Funders
- Norges Forskningsråd (223273)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (32003B_159780, 31003A_160203)
- Simons Foundation (SFARI274424)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- 16p11.2 deletion, 16p11.2 duplication, dose-response relationship, intracranial volume, basal ganglia, caudate nucleus, globus pallidus, putamen, accumbens, subcortical volume, neurodevelopmental disorders, autism spectrum disorder, schizophrenia, Full Scale IQ, neuropathology
- MeSH terms
- Autism Spectrum Disorder, Adult, Autistic Disorder, Basal Ganglia, Brain, Chromosome Deletion, Chromosomes, Human, Pair 16, Female, Globus Pallidus, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Intellectual Disability, Middle Aged, Organ Size, Putamen, Schizophrenia, Databases, Factual, Chromosome Disorders, DNA Copy Number Variations, Chromosome Duplication, Neurodevelopmental Disorders
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