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

for the 16p11.2 European Consortium, for the 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

for the 16p11.2 European Consortium, for the ENIGMA-CNV working group

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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
Issue number	3
DOIs	https://doi.org/10.1038/s41380-018-0118-1
State	Published - 1 Mar 2020
Externally published	Yes

Funding

Funders	Funder number
European Commission
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, 115300, 230374, 602450, 278948, 603016
Horizon 2020 Framework Programme	695313, 667302, 677467, 643051
Japan Society for the Promotion of Science	16H03305, 19H05467, 18KT0022
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	31003A_160203, 156791, 32003B_159780
Simons Foundation	SFARI274424
Not added	480-04-004
National Institute of Biomedical Imaging and Bioengineering	R01EB005846, R01EB000840, U54EB020403, R01EB006841
UK Research and Innovation	MR/N000390/1
National Institute of General Medical Sciences	P20GM103472
National Health and Medical Research Council	389875, 1083656, 401184, 1009064, 401162
Norges Forskningsråd	223273
Agence Nationale de la Recherche	ANR-12-SAMA-0004
Not added	12/IP/1359, 16/ERCD/3797

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10.1038/s41380-018-0118-1

Cite this

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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.",

author = "{for the 16p11.2 European Consortium, for the ENIGMA-CNV working group} and S{\o}nderby, {Ida E.} and {\'O}mar G{\'u}stafsson and Doan, {Nhat Trung} and Hibar, {Derrek P.} and Sandra Martin-Brevet and Abdel Abdellaoui and David Ames and Katrin Amunts and Michael Andersson and Armstrong, {Nicola J.} and Manon Bernard and Nicholas Blackburn and John Blangero and Boomsma, {Dorret I.} and Janita Bralten and Brattbak, {Hans Richard} and Henry Brodaty and Brouwer, {Rachel M.} and Robin B{\"u}low and Vince Calhoun and Svenja Caspers and Gianpiero Cavalleri and Chen, {Chi Hua} and Sven Cichon and Simone Ciufolini and Aiden Corvin and Benedicto Crespo-Facorro and Curran, {Joanne E.} and Dale, {Anders M.} and Shareefa Dalvie and Paola Dazzan and {de Geus}, {Eco J.C.} and {de Zubicaray}, {Greig I.} and {de Zwarte}, {Sonja M.C.} and Norman Delanty and {den Braber}, Anouk and Sylvane Desrivi{\`e}res and Gary Donohoe and Bogdan Draganski and Stefan Ehrlich and Thomas Espeseth and Fisher, {Simon E.} and Barbara Franke and Vincent Frouin and Masaki Fukunaga and Thomas Gareau and Glahn, {David C.} and Hans Grabe and Groenewold, {Nynke A.} and Stein, {Dan J.}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2020",

month = mar,

day = "1",

doi = "10.1038/s41380-018-0118-1",

language = "אנגלית",

volume = "25",

pages = "584--602",

journal = "Molecular Psychiatry",

issn = "1359-4184",

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TY - JOUR

T1 - Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

AU - for the 16p11.2 European Consortium, for the ENIGMA-CNV working group

AU - Sønderby, Ida E.

AU - Gústafsson, Ómar

AU - Doan, Nhat Trung

AU - Hibar, Derrek P.

AU - Martin-Brevet, Sandra

AU - Abdellaoui, Abdel

AU - Ames, David

AU - Amunts, Katrin

AU - Andersson, Michael

AU - Armstrong, Nicola J.

AU - Bernard, Manon

AU - Blackburn, Nicholas

AU - Blangero, John

AU - Boomsma, Dorret I.

AU - Bralten, Janita

AU - Brattbak, Hans Richard

AU - Brodaty, Henry

AU - Brouwer, Rachel M.

AU - Bülow, Robin

AU - Calhoun, Vince

AU - Caspers, Svenja

AU - Cavalleri, Gianpiero

AU - Chen, Chi Hua

AU - Cichon, Sven

AU - Ciufolini, Simone

AU - Corvin, Aiden

AU - Crespo-Facorro, Benedicto

AU - Curran, Joanne E.

AU - Dale, Anders M.

AU - Dalvie, Shareefa

AU - Dazzan, Paola

AU - de Geus, Eco J.C.

AU - de Zubicaray, Greig I.

AU - de Zwarte, Sonja M.C.

AU - Delanty, Norman

AU - den Braber, Anouk

AU - Desrivières, Sylvane

AU - Donohoe, Gary

AU - Draganski, Bogdan

AU - Ehrlich, Stefan

AU - Espeseth, Thomas

AU - Fisher, Simon E.

AU - Franke, Barbara

AU - Frouin, Vincent

AU - Fukunaga, Masaki

AU - Gareau, Thomas

AU - Glahn, David C.

AU - Grabe, Hans

AU - Groenewold, Nynke A.

AU - Stein, Dan J.

PY - 2020/3/1

Y1 - 2020/3/1

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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EP - 602

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 3

ER -

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

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