1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Ida E. Sonderby; Dennis van der Meer; Clara Moreau; Tobias Kaufmann; G. Bragi Walters; Maria Ellegaard; Abdel Abdellaoui; David Ames; Katrin Amunts; Micael Andersson; Nicola J. Armstrong; Manon Bernard; Nicholas B. Blackburn; John Blangero; Dorret I. Boomsma; Henry Brodaty; Rachel M. Brouwer; Robin Buelow; Rune Boen; Wiepke Cahn; Vince D. Calhoun; Svenja Caspers; Christopher R. K. Ching; Sven Cichon; Simone Ciufolini; Benedicto Crespo-Facorro; Joanne E. Curran; Anders M. Dale; Shareefa Dalvie; Paola Dazzan; Eco J. C. de Geus; Greig I. de Zubicaray; Sonja M. C. de Zwarte; Sylvane Desrivieres; Joanne L. Doherty; Gary Donohoe; Bogdan Draganski; Stefan Ehrlich; Else Eising; Thomas Espeseth; Kim Fejgin; Simon E. Fisher; Tormod Fladby; Oleksandr Frei; Vincent Frouin; Masaki Fukunaga; Thomas Gareau; David E. J. Linden; Jennifer Monereo Sanchez; Ana I. Silva; ENIGMA-CNV Working Group

doi:10.1038/s41398-021-01213-0

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Ida E. Sonderby^*, Dennis van der Meer, Clara Moreau, Tobias Kaufmann, G. Bragi Walters, Maria Ellegaard, Abdel Abdellaoui, David Ames, Katrin Amunts, Micael Andersson, Nicola J. Armstrong, Manon Bernard, Nicholas B. Blackburn, John Blangero, Dorret I. Boomsma, Henry Brodaty, Rachel M. Brouwer, Robin Buelow, Rune Boen, Wiepke CahnVince D. Calhoun, Svenja Caspers, Christopher R. K. Ching, Sven Cichon, Simone Ciufolini, Benedicto Crespo-Facorro, Joanne E. Curran, Anders M. Dale, Shareefa Dalvie, Paola Dazzan, Eco J. C. de Geus, Greig I. de Zubicaray, Sonja M. C. de Zwarte, Sylvane Desrivieres, Joanne L. Doherty, Gary Donohoe, Bogdan Draganski, Stefan Ehrlich, Else Eising, Thomas Espeseth, Kim Fejgin, Simon E. Fisher, Tormod Fladby, Oleksandr Frei, Vincent Frouin, Masaki Fukunaga, Thomas Gareau, David E. J. Linden, Jennifer Monereo Sanchez, Ana I. Silva, ENIGMA-CNV Working Group

^*Corresponding author for this work

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

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Original language	English
Article number	182
Number of pages	16
Journal	Translational Psychiatry
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41398-021-01213-0
Publication status	Published - 22 Mar 2021

Keywords

CHROMOSOME 1Q21.1
BRAIN
GENOME
MICRODUPLICATION
MICRODELETIONS
REARRANGEMENTS
ABNORMALITIES
DUPLICATIONS
PHENOTYPE
EXPANSION

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Cite this

Sonderby, I. E., van der Meer, D., Moreau, C., Kaufmann, T., Walters, G. B., Ellegaard, M., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N. B., Blangero, J., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Buelow, R., Boen, R., ... ENIGMA-CNV Working Group (2021). 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans. Translational Psychiatry, 11(1), Article 182. https://doi.org/10.1038/s41398-021-01213-0

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title = "1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans",

abstract = "Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.",

keywords = "CHROMOSOME 1Q21.1, BRAIN, GENOME, MICRODUPLICATION, MICRODELETIONS, REARRANGEMENTS, ABNORMALITIES, DUPLICATIONS, PHENOTYPE, EXPANSION",

author = "Sonderby, {Ida E.} and {van der Meer}, Dennis and Clara Moreau and Tobias Kaufmann and Walters, {G. Bragi} and Maria Ellegaard and Abdel Abdellaoui and David Ames and Katrin Amunts and Micael Andersson and Armstrong, {Nicola J.} and Manon Bernard and Blackburn, {Nicholas B.} and John Blangero and Boomsma, {Dorret I.} and Henry Brodaty and Brouwer, {Rachel M.} and Robin Buelow and Rune Boen and Wiepke Cahn and Calhoun, {Vince D.} and Svenja Caspers and Ching, {Christopher R. K.} and Sven Cichon and Simone Ciufolini 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 Sylvane Desrivieres and Doherty, {Joanne L.} and Gary Donohoe and Bogdan Draganski and Stefan Ehrlich and Else Eising and Thomas Espeseth and Kim Fejgin and Fisher, {Simon E.} and Tormod Fladby and Oleksandr Frei and Vincent Frouin and Masaki Fukunaga and Thomas Gareau and Linden, {David E. J.} and Sanchez, {Jennifer Monereo} and Silva, {Ana I.} and {ENIGMA-CNV Working Group}",

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month = mar,

day = "22",

doi = "10.1038/s41398-021-01213-0",

language = "English",

volume = "11",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

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Sonderby, IE, van der Meer, D, Moreau, C, Kaufmann, T, Walters, GB, Ellegaard, M, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB, Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Buelow, R, Boen, R, Cahn, W, Calhoun, VD, Caspers, S, Ching, CRK, Cichon, S, Ciufolini, S, Crespo-Facorro, B, Curran, JE, Dale, AM, Dalvie, S, Dazzan, P, de Geus, EJC, de Zubicaray, GI, de Zwarte, SMC, Desrivieres, S, Doherty, JL, Donohoe, G, Draganski, B, Ehrlich, S, Eising, E, Espeseth, T, Fejgin, K, Fisher, SE, Fladby, T, Frei, O, Frouin, V, Fukunaga, M, Gareau, T, Linden, DEJ, Sanchez, JM, Silva, AI & ENIGMA-CNV Working Group 2021, '1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans', Translational Psychiatry, vol. 11, no. 1, 182. https://doi.org/10.1038/s41398-021-01213-0

TY - JOUR

T1 - 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

AU - Sonderby, Ida E.

AU - van der Meer, Dennis

AU - Moreau, Clara

AU - Kaufmann, Tobias

AU - Walters, G. Bragi

AU - Ellegaard, Maria

AU - Abdellaoui, Abdel

AU - Ames, David

AU - Amunts, Katrin

AU - Andersson, Micael

AU - Armstrong, Nicola J.

AU - Bernard, Manon

AU - Blackburn, Nicholas B.

AU - Blangero, John

AU - Boomsma, Dorret I.

AU - Brodaty, Henry

AU - Brouwer, Rachel M.

AU - Buelow, Robin

AU - Boen, Rune

AU - Cahn, Wiepke

AU - Calhoun, Vince D.

AU - Caspers, Svenja

AU - Ching, Christopher R. K.

AU - Cichon, Sven

AU - Ciufolini, Simone

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 - Desrivieres, Sylvane

AU - Doherty, Joanne L.

AU - Donohoe, Gary

AU - Draganski, Bogdan

AU - Ehrlich, Stefan

AU - Eising, Else

AU - Espeseth, Thomas

AU - Fejgin, Kim

AU - Fisher, Simon E.

AU - Fladby, Tormod

AU - Frei, Oleksandr

AU - Frouin, Vincent

AU - Fukunaga, Masaki

AU - Gareau, Thomas

AU - Linden, David E. J.

AU - Sanchez, Jennifer Monereo

AU - Silva, Ana I.

AU - ENIGMA-CNV Working Group

PY - 2021/3/22

Y1 - 2021/3/22

N2 - Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

AB - Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

KW - CHROMOSOME 1Q21.1

KW - BRAIN

KW - GENOME

KW - MICRODUPLICATION

KW - MICRODELETIONS

KW - REARRANGEMENTS

KW - ABNORMALITIES

KW - DUPLICATIONS

KW - PHENOTYPE

KW - EXPANSION

U2 - 10.1038/s41398-021-01213-0

DO - 10.1038/s41398-021-01213-0

M3 - Article

C2 - 33753722

SN - 2158-3188

VL - 11

JO - Translational Psychiatry

JF - Translational Psychiatry

IS - 1

M1 - 182

ER -