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

Ida Elken Sønderby; Ole A. Andreassen; A. Abdellaoui; D.I. Boomsma; Eco JC de Geus; A. den Braber; J.J. Hottenga; Brenda W J H Penninx; Yuri Milaneschi; D. van t Ent; ENIGMA-CNV working group

doi:10.1038/s41380-018-0118-1

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

Ida Elken Sønderby
, Ole A. Andreassen^*
, A. Abdellaoui
, D.I. Boomsma
, Eco JC de Geus
, A. den Braber
, J.J. Hottenga
, Brenda W J H Penninx
, Yuri Milaneschi
, D. van t Ent
, ENIGMA-CNV working group

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	584-602
Number of pages	19
Journal	Molecular Psychiatry
Volume	25
Early online date	3 Oct 2018
DOIs	https://doi.org/10.1038/s41380-018-0118-1
Publication status	Published - Mar 2020

Funding

Funders	Funder number
European Commission
UK Research and Innovation
National Institute of Mental Health	R01MH081802, R01MH085772, RC1MH089257, K08MH068540, R01MH078111, RC2MH089951, RC2MH089995, R01MH083824
National Institute of Child Health and Human Development	R01HD050735
National Center for Research Resources	M01RR001066, P41RR014075, U24RR021992, P20RR021938
Seventh Framework Programme	268800, 602805, 230374, 602450, 115300, 278948, 603016
Agence Nationale de la Recherche	ANR-12-SAMA-0004
Japan Society for the Promotion of Science	16H03305, 19H05467
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	31003A_160203, 156791, 32003B_159780
Simons Foundation	SFARI274424
Medical Research Council	MR/N000390/1
National Institute of Biomedical Imaging and Bioengineering	R01EB005846, R01EB000840, U54EB020403, R01EB006841
Horizon 2020 Framework Programme	695313, 667302, 677467, 643051
???publication-publication-funding-organisation-not-added???	12/IP/1359, 16/ERCD/3797
National Institute of General Medical Sciences	P20GM103472
Norges Forskningsråd	223273
???publication-publication-funding-organisation-not-added???	480-04-004
National Health and Medical Research Council	389875, 1083656, 401162, 1009064, 401184

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 17 Partnerships for the Goals

Cohort Studies

Netherlands Twin Register (NTR)

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10.1038/s41380-018-0118-1

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Sønderby, I. E., Andreassen, O. A., Abdellaoui, A., Boomsma, D. I., de Geus, E. JC., den Braber, A., Hottenga, J. J., W J H Penninx, B., Milaneschi, Y., van t Ent, D., & ENIGMA-CNV working group (2020). Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. Molecular Psychiatry, 25, 584-602. https://doi.org/10.1038/s41380-018-0118-1

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

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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AU - Sønderby, Ida Elken

AU - Gústafsson, Ómar

AU - Doan, Nhat Trung

AU - Hibar, Derrek Paul

AU - Martin-Brevet, Sandra

AU - Westlye, Lars T.

AU - Jacquemont, Sébastien

AU - Djurovic, Srdjan

AU - Stefánsson, Hreinn

AU - Stefánsson, Kari

AU - Thompson, Paul M.

AU - Andreassen, Ole A.

AU - Abdellaoui, A.

AU - Boomsma, D.I.

AU - de Geus, Eco JC

AU - den Braber, A.

AU - Hottenga, J.J.

AU - W J H Penninx, Brenda

AU - Milaneschi, Yuri

AU - van t Ent, D.

AU - ENIGMA-CNV working group

PY - 2020/3

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N2 - 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.

AB - 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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ER -

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

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

Cite this