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

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

Research output: Contribution to JournalArticleAcademicpeer-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 languageEnglish
JournalMolecular Psychiatry
DOIs
Publication statusE-pub ahead of print - 3 Oct 2018

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Basal Ganglia
Globus Pallidus
Putamen
Brain
Schizophrenia
Magnetic Resonance Imaging

Cite this

@article{342eb1c07fcc4a31981949a6908d6bbd,
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 = "S{\o}nderby, {Ida Elken} and {\'O}mar G{\'u}stafsson and Doan, {Nhat Trung} and Hibar, {Derrek Paul} and Sandra Martin-Brevet and Westlye, {Lars T.} and S{\'e}bastien Jacquemont and Srdjan Djurovic and Hreinn Stef{\'a}nsson and Kari Stef{\'a}nsson and Thompson, {Paul M.} and Andreassen, {Ole A.} and A. Abdellaoui and D.I. Boomsma and {de Geus}, {Eco JC} and {den Braber}, A. and J.J. Hottenga and {W J H Penninx}, Brenda and Yuri Milaneschi and {van t Ent}, D. and {ENIGMA-CNV working group}",
year = "2018",
month = "10",
day = "3",
doi = "10.1038/s41380-018-0118-1",
language = "English",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",

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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. / Abdellaoui, A.; Boomsma, D.I.; de Geus, Eco JC; den Braber, A.; Hottenga, J.J.; W J H Penninx, Brenda; Milaneschi, Yuri; van t Ent, D.; ENIGMA-CNV working group.

In: Molecular Psychiatry, 03.10.2018.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

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

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 - 2018/10/3

Y1 - 2018/10/3

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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