Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region with Cortical and Subcortical Morphology and Cognition

Dennis Van Der Meer; Ida E. Sønderby; Tobias Kaufmann; G. Bragi Walters; 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 Bülow; Wiepke Cahn; Vince D. Calhoun; Svenja Caspers; Gianpiero L. Cavalleri; Christopher R.K. Ching; Sven Cichon; Simone Ciufolini; Aiden Corvin; Benedicto Crespo-Facorro; Joanne E. Curran; Shareefa Dalvie; Paola Dazzan; Eco J.C. De Geus; Greig I. De Zubicaray; Sonja M.C. De Zwarte; Norman Delanty; Anouk Den Braber; Sylvane Desrivieres; Marta Di Forti; Joanne L. Doherty; Gary Donohoe; Stefan Ehrlich; Else Eising; Thomas Espeseth; Simon E. Fisher; Tormod Fladby; Oleksandr Frei; Vincent Frouin; Masaki Fukunaga; Thomas Gareau; David C. Glahn; Hans J. Grabe; Nynke A. Groenewold; Ómar Gústafsson; Jan Haavik; Asta K. Haberg; Ryota Hashimoto; Jayne Y. Hehir-Kwa; Derrek P. Hibar; Manon H.J. Hillegers; Per Hoffmann; Laurena Holleran; Jouke Jan Hottenga; Hilleke E. Hulshoff Pol; Masashi Ikeda; Sébastien Jacquemont; Neda Jahanshad; Christiane Jockwitz; Stefan Johansson; Erik G. Jönsson; Masataka Kikuchi; Emma E.M. Knowles; John B. Kwok; Stephanie Le Hellard; David E.J. Linden; Jingyu Liu; Arvid Lundervold; Astri J. Lundervold; Nicholas G. Martin; Karen A. Mather; Samuel R. Mathias; Katie L. McMahon; Allan F. McRae; Sarah E. Medland; Torgeir Moberget; Clara Moreau; Derek W. Morris; Thomas W. Mühleisen; Robin M. Murray; Jan E. Nordvik; Lars Nyberg; Loes M. Olde Loohuis; Roel A. Ophoff; Michael J. Owen; Tomas Paus; Zdenka Pausova; Juan M. Peralta; Bruce Pike; Carlos Prieto; Erin Burke Quinlan; Céline S. Reinbold; Tiago Reis Marques; James J.H. Rucker; Perminder S. Sachdev; Sigrid B. Sando; Peter R. Schofield; Andrew J. Schork; Gunter Schumann; Jean Shin; Elena Shumskaya; Ana I. Silva; Sanjay M. Sisodiya; Vidar M. Steen; Dan J. Stein; Lachlan T. Strike; Christian K. Tamnes; Alexander Teumer; Anbupalam Thalamuthu; Diana Tordesillas-Gutiérrez; Anne Uhlmann; Magnús Úlfarsson; Dennis Van 'T Ent; Marianne B.M. Van Den Bree; Evangelos Vassos; Wei Wen; Katharina Wittfeld; Margaret J. Wright; Tetyana Zayats; Anders M. Dale; Srdjan Djurovic; Ingrid Agartz; Lars T. Westlye; Hreinn Stefánsson; Kári Stefánsson; Paul M. Thompson; Ole A. Andreassen

doi:10.1001/jamapsychiatry.2019.3779

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region with Cortical and Subcortical Morphology and Cognition

Dennis Van Der Meer
, Ida E. Sønderby
, Tobias Kaufmann
, G. Bragi Walters
, 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 Bülow
, Wiepke Cahn
, Vince D. Calhoun
, Svenja Caspers
, Gianpiero L. Cavalleri

Christopher R.K. Ching, Sven Cichon, Simone Ciufolini, Aiden Corvin, Benedicto Crespo-Facorro, Joanne E. Curran, Shareefa Dalvie, Paola Dazzan, Eco J.C. De Geus, Greig I. De Zubicaray, Sonja M.C. De Zwarte, Norman Delanty, Anouk Den Braber, Sylvane Desrivieres, Marta Di Forti, Joanne L. Doherty, Gary Donohoe, Stefan Ehrlich, Else Eising, Thomas Espeseth, Simon E. Fisher, Tormod Fladby, Oleksandr Frei, Vincent Frouin, Masaki Fukunaga, Thomas Gareau, David C. Glahn, Hans J. Grabe, Nynke A. Groenewold, Ómar Gústafsson, Jan Haavik, Asta K. Haberg, Ryota Hashimoto, Jayne Y. Hehir-Kwa, Derrek P. Hibar, Manon H.J. Hillegers, Per Hoffmann, Laurena Holleran, Jouke Jan Hottenga, Hilleke E. Hulshoff Pol, Masashi Ikeda, Sébastien Jacquemont, Neda Jahanshad, Christiane Jockwitz, Stefan Johansson, Erik G. Jönsson, Masataka Kikuchi, Emma E.M. Knowles, John B. Kwok, Stephanie Le Hellard, David E.J. Linden, Jingyu Liu, Arvid Lundervold, Astri J. Lundervold, Nicholas G. Martin, Karen A. Mather, Samuel R. Mathias, Katie L. McMahon, Allan F. McRae, Sarah E. Medland, Torgeir Moberget, Clara Moreau, Derek W. Morris, Thomas W. Mühleisen, Robin M. Murray, Jan E. Nordvik, Lars Nyberg, Loes M. Olde Loohuis, Roel A. Ophoff, Michael J. Owen, Tomas Paus, Zdenka Pausova, Juan M. Peralta, Bruce Pike, Carlos Prieto, Erin Burke Quinlan, Céline S. Reinbold, Tiago Reis Marques, James J.H. Rucker, Perminder S. Sachdev, Sigrid B. Sando, Peter R. Schofield, Andrew J. Schork, Gunter Schumann, Jean Shin, Elena Shumskaya, Ana I. Silva, Sanjay M. Sisodiya, Vidar M. Steen, Dan J. Stein, Lachlan T. Strike, Christian K. Tamnes, Alexander Teumer, Anbupalam Thalamuthu, Diana Tordesillas-Gutiérrez, Anne Uhlmann, Magnús Úlfarsson, Dennis Van 'T Ent, Marianne B.M. Van Den Bree, Evangelos Vassos, Wei Wen, Katharina Wittfeld, Margaret J. Wright, Tetyana Zayats, Anders M. Dale, Srdjan Djurovic, Ingrid Agartz, Lars T. Westlye, Hreinn Stefánsson, Kári Stefánsson, Paul M. Thompson, Ole A. Andreassen^*

^*Corresponding author for this work

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Abstract

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age², sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Results: Of 45756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10^-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10^-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10^-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10^-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

Original language	English
Pages (from-to)	420-430
Number of pages	11
Journal	JAMA Psychiatry
Volume	77
Issue number	4
DOIs	https://doi.org/10.1001/jamapsychiatry.2019.3779
Publication status	Published - 30 Oct 2019
Externally published	Yes

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10.1001/jamapsychiatry.2019.3779

Cite this

Van Der Meer, D., Sønderby, I. E., Kaufmann, T., Walters, G. B., 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., Bülow, R., Cahn, W., Calhoun, V. D., Caspers, S., ... Andreassen, O. A. (2019). Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region with Cortical and Subcortical Morphology and Cognition. JAMA Psychiatry, 77(4), 420-430. https://doi.org/10.1001/jamapsychiatry.2019.3779

@article{59e137511ed9429885a91c074c5a920f,

title = "Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region with Cortical and Subcortical Morphology and Cognition",

abstract = "Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5\% to 1.0\% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Results: Of 45756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23754 (51.9\%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.",

author = "\{Van Der Meer\}, Dennis and S{\o}nderby, \{Ida E.\} and Tobias Kaufmann and Walters, \{G. Bragi\} 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 B{\"u}low and Wiepke Cahn and Calhoun, \{Vince D.\} and Svenja Caspers and Cavalleri, \{Gianpiero L.\} and Ching, \{Christopher R.K.\} and Sven Cichon and Simone Ciufolini and Aiden Corvin and Benedicto Crespo-Facorro and Curran, \{Joanne E.\} 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 Desrivieres and \{Di Forti\}, Marta and Doherty, \{Joanne L.\} and Gary Donohoe and Stefan Ehrlich and Else Eising and Thomas Espeseth and Fisher, \{Simon E.\} and Tormod Fladby and Oleksandr Frei and Vincent Frouin and Masaki Fukunaga and Thomas Gareau and Glahn, \{David C.\} and Grabe, \{Hans J.\} and Groenewold, \{Nynke A.\} and {\'O}mar G{\'u}stafsson and Jan Haavik and Haberg, \{Asta K.\} and Ryota Hashimoto and Hehir-Kwa, \{Jayne Y.\} and Hibar, \{Derrek P.\} and Hillegers, \{Manon H.J.\} and Per Hoffmann and Laurena Holleran and Hottenga, \{Jouke Jan\} and \{Hulshoff Pol\}, \{Hilleke E.\} and Masashi Ikeda and S{\'e}bastien Jacquemont and Neda Jahanshad and Christiane Jockwitz and Stefan Johansson and J{\"o}nsson, \{Erik G.\} and Masataka Kikuchi and Knowles, \{Emma E.M.\} and Kwok, \{John B.\} and \{Le Hellard\}, Stephanie and Linden, \{David E.J.\} and Jingyu Liu and Arvid Lundervold and Lundervold, \{Astri J.\} and Martin, \{Nicholas G.\} and Mather, \{Karen A.\} and Mathias, \{Samuel R.\} and McMahon, \{Katie L.\} and McRae, \{Allan F.\} and Medland, \{Sarah E.\} and Torgeir Moberget and Clara Moreau and Morris, \{Derek W.\} and M{\"u}hleisen, \{Thomas W.\} and Murray, \{Robin M.\} and Nordvik, \{Jan E.\} and Lars Nyberg and \{Olde Loohuis\}, \{Loes M.\} and Ophoff, \{Roel A.\} and Owen, \{Michael J.\} and Tomas Paus and Zdenka Pausova and Peralta, \{Juan M.\} and Bruce Pike and Carlos Prieto and Quinlan, \{Erin Burke\} and Reinbold, \{C{\'e}line S.\} and \{Reis Marques\}, Tiago and Rucker, \{James J.H.\} and Sachdev, \{Perminder S.\} and Sando, \{Sigrid B.\} and Schofield, \{Peter R.\} and Schork, \{Andrew J.\} and Gunter Schumann and Jean Shin and Elena Shumskaya and Silva, \{Ana I.\} and Sisodiya, \{Sanjay M.\} and Steen, \{Vidar M.\} and Stein, \{Dan J.\} and Strike, \{Lachlan T.\} and Tamnes, \{Christian K.\} and Alexander Teumer and Anbupalam Thalamuthu and Diana Tordesillas-Guti{\'e}rrez and Anne Uhlmann and Magn{\'u}s {\'U}lfarsson and \{Van 'T Ent\}, Dennis and \{Van Den Bree\}, \{Marianne B.M.\} and Evangelos Vassos and Wei Wen and Katharina Wittfeld and Wright, \{Margaret J.\} and Tetyana Zayats and Dale, \{Anders M.\} and Srdjan Djurovic and Ingrid Agartz and Westlye, \{Lars T.\} and Hreinn Stef{\'a}nsson and K{\'a}ri Stef{\'a}nsson and Thompson, \{Paul M.\} and Andreassen, \{Ole A.\}",

year = "2019",

month = oct,

day = "30",

doi = "10.1001/jamapsychiatry.2019.3779",

language = "English",

volume = "77",

pages = "420--430",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "4",

}

Van Der Meer, D, Sønderby, IE, Kaufmann, T, Walters, GB, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB, Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Bülow, R, Cahn, W, Calhoun, VD, Caspers, S, Cavalleri, GL, Ching, CRK, Cichon, S, Ciufolini, S, Corvin, A, Crespo-Facorro, B, Curran, JE, Dalvie, S, Dazzan, P, De Geus, EJC, De Zubicaray, GI, De Zwarte, SMC, Delanty, N, Den Braber, A, Desrivieres, S, Di Forti, M, Doherty, JL, Donohoe, G, Ehrlich, S, Eising, E, Espeseth, T, Fisher, SE, Fladby, T, Frei, O, Frouin, V, Fukunaga, M, Gareau, T, Glahn, DC, Grabe, HJ, Groenewold, NA, Gústafsson, Ó, Haavik, J, Haberg, AK, Hashimoto, R, Hehir-Kwa, JY, Hibar, DP, Hillegers, MHJ, Hoffmann, P, Holleran, L, Hottenga, JJ, Hulshoff Pol, HE, Ikeda, M, Jacquemont, S, Jahanshad, N, Jockwitz, C, Johansson, S, Jönsson, EG, Kikuchi, M, Knowles, EEM, Kwok, JB, Le Hellard, S, Linden, DEJ, Liu, J, Lundervold, A, Lundervold, AJ, Martin, NG, Mather, KA, Mathias, SR, McMahon, KL, McRae, AF, Medland, SE, Moberget, T, Moreau, C, Morris, DW, Mühleisen, TW, Murray, RM, Nordvik, JE, Nyberg, L, Olde Loohuis, LM, Ophoff, RA, Owen, MJ, Paus, T, Pausova, Z, Peralta, JM, Pike, B, Prieto, C, Quinlan, EB, Reinbold, CS, Reis Marques, T, Rucker, JJH, Sachdev, PS, Sando, SB, Schofield, PR, Schork, AJ, Schumann, G, Shin, J, Shumskaya, E, Silva, AI, Sisodiya, SM, Steen, VM, Stein, DJ, Strike, LT, Tamnes, CK, Teumer, A, Thalamuthu, A, Tordesillas-Gutiérrez, D, Uhlmann, A, Úlfarsson, M, Van 'T Ent, D, Van Den Bree, MBM, Vassos, E, Wen, W, Wittfeld, K, Wright, MJ, Zayats, T, Dale, AM, Djurovic, S, Agartz, I, Westlye, LT, Stefánsson, H, Stefánsson, K, Thompson, PM & Andreassen, OA 2019, 'Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region with Cortical and Subcortical Morphology and Cognition', JAMA Psychiatry, vol. 77, no. 4, pp. 420-430. https://doi.org/10.1001/jamapsychiatry.2019.3779

TY - JOUR

T1 - Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region with Cortical and Subcortical Morphology and Cognition

AU - Van Der Meer, Dennis

AU - Sønderby, Ida E.

AU - Kaufmann, Tobias

AU - Walters, G. Bragi

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 - Bülow, Robin

AU - Cahn, Wiepke

AU - Calhoun, Vince D.

AU - Caspers, Svenja

AU - Cavalleri, Gianpiero L.

AU - Ching, Christopher R.K.

AU - Cichon, Sven

AU - Ciufolini, Simone

AU - Corvin, Aiden

AU - Crespo-Facorro, Benedicto

AU - Curran, Joanne E.

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 - Desrivieres, Sylvane

AU - Di Forti, Marta

AU - Doherty, Joanne L.

AU - Donohoe, Gary

AU - Ehrlich, Stefan

AU - Eising, Else

AU - Espeseth, Thomas

AU - Fisher, Simon E.

AU - Fladby, Tormod

AU - Frei, Oleksandr

AU - Frouin, Vincent

AU - Fukunaga, Masaki

AU - Gareau, Thomas

AU - Glahn, David C.

AU - Grabe, Hans J.

AU - Groenewold, Nynke A.

AU - Gústafsson, Ómar

AU - Haavik, Jan

AU - Haberg, Asta K.

AU - Hashimoto, Ryota

AU - Hehir-Kwa, Jayne Y.

AU - Hibar, Derrek P.

AU - Hillegers, Manon H.J.

AU - Hoffmann, Per

AU - Holleran, Laurena

AU - Hottenga, Jouke Jan

AU - Hulshoff Pol, Hilleke E.

AU - Ikeda, Masashi

AU - Jacquemont, Sébastien

AU - Jahanshad, Neda

AU - Jockwitz, Christiane

AU - Johansson, Stefan

AU - Jönsson, Erik G.

AU - Kikuchi, Masataka

AU - Knowles, Emma E.M.

AU - Kwok, John B.

AU - Le Hellard, Stephanie

AU - Linden, David E.J.

AU - Liu, Jingyu

AU - Lundervold, Arvid

AU - Lundervold, Astri J.

AU - Martin, Nicholas G.

AU - Mather, Karen A.

AU - Mathias, Samuel R.

AU - McMahon, Katie L.

AU - McRae, Allan F.

AU - Medland, Sarah E.

AU - Moberget, Torgeir

AU - Moreau, Clara

AU - Morris, Derek W.

AU - Mühleisen, Thomas W.

AU - Murray, Robin M.

AU - Nordvik, Jan E.

AU - Nyberg, Lars

AU - Olde Loohuis, Loes M.

AU - Ophoff, Roel A.

AU - Owen, Michael J.

AU - Paus, Tomas

AU - Pausova, Zdenka

AU - Peralta, Juan M.

AU - Pike, Bruce

AU - Prieto, Carlos

AU - Quinlan, Erin Burke

AU - Reinbold, Céline S.

AU - Reis Marques, Tiago

AU - Rucker, James J.H.

AU - Sachdev, Perminder S.

AU - Sando, Sigrid B.

AU - Schofield, Peter R.

AU - Schork, Andrew J.

AU - Schumann, Gunter

AU - Shin, Jean

AU - Shumskaya, Elena

AU - Silva, Ana I.

AU - Sisodiya, Sanjay M.

AU - Steen, Vidar M.

AU - Stein, Dan J.

AU - Strike, Lachlan T.

AU - Tamnes, Christian K.

AU - Teumer, Alexander

AU - Thalamuthu, Anbupalam

AU - Tordesillas-Gutiérrez, Diana

AU - Uhlmann, Anne

AU - Úlfarsson, Magnús

AU - Van 'T Ent, Dennis

AU - Van Den Bree, Marianne B.M.

AU - Vassos, Evangelos

AU - Wen, Wei

AU - Wittfeld, Katharina

AU - Wright, Margaret J.

AU - Zayats, Tetyana

AU - Dale, Anders M.

AU - Djurovic, Srdjan

AU - Agartz, Ingrid

AU - Westlye, Lars T.

AU - Stefánsson, Hreinn

AU - Stefánsson, Kári

AU - Thompson, Paul M.

AU - Andreassen, Ole A.

PY - 2019/10/30

Y1 - 2019/10/30

N2 - Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Results: Of 45756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

AB - Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Results: Of 45756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

UR - https://www.scopus.com/pages/publications/85074651799

U2 - 10.1001/jamapsychiatry.2019.3779

DO - 10.1001/jamapsychiatry.2019.3779

M3 - Article

C2 - 31665216

AN - SCOPUS:85074651799

SN - 2168-622X

VL - 77

SP - 420

EP - 430

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 4

ER -

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region with Cortical and Subcortical Morphology and Cognition

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