Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
ENIGMA-CNV Working Group: van der Meer, Dennis; Sonderby, Ida E; Kaufmann, Tobias; Walters, G Bragi; Abdellaoui, Abdel; Ames, David; Amunts, Katrin; Andersson, Micael; Armstrong, Nicola J; Bernard, Manon; Blackburn, Nicholas B; Blangero, John; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Bu...
Published in: | JAMA Psychiatry |
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Format: | Article in Journal/Newspaper |
Language: | English |
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American Medical Association
2020
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Online Access: | http://hdl.handle.net/10261/236107 https://doi.org/10.1001/jamapsychiatry.2019.3779 |
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ENIGMA-CNV Working Group: van der Meer, Dennis; Sonderby, Ida E; Kaufmann, Tobias; Walters, G Bragi; Abdellaoui, Abdel; Ames, David; Amunts, Katrin; Andersson, Micael; Armstrong, Nicola J; Bernard, Manon; Blackburn, Nicholas B; Blangero, John; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Bulow, Robin; Cahn, Wiepke; Calhoun, Vince D; Caspers, Svenja; Cavalleri, Gianpiero L; Ching, Christopher R K; Cichon, Sven; Ciufolini, Simone; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Dalvie, Shareefa; Dazzan, Paola; de Geus, Eco J C; de Zubicaray, Greig I; de Zwarte, Sonja M C; Delanty, Norman; den Braber, Anouk; Desrivieres, Sylvane; Di Forti, Marta; Doherty, Joanne L; Donohoe, Gary; Ehrlich, Stefan; Eising, Else; Espeseth, Thomas; Fisher, Simon E; Fladby, Tormod; Frei, Oleksandr; Frouin, Vincent; Fukunaga, Masaki; Gareau, Thomas; Glahn, David C; Grabe, Hans J; Groenewold, Nynke A; Gustafsson, Omar; Haavik, Jan; Haberg, Asta K; Hashimoto, Ryota; Hehir-Kwa, Jayne Y; Hibar, Derrek P; Hillegers, Manon H J; Hoffmann, Per; Holleran, Laurena; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Jacquemont, Sebastien; Jahanshad, Neda; Jockwitz, Christiane; Johansson, Stefan; Jonsson, Erik G; Kikuchi, Masataka; Knowles, Emma E M; Kwok, John B; Le Hellard, Stephanie; Linden, David E J; Liu, Jingyu; Lundervold, Arvid; Lundervold, Astri J; Martin, Nicholas G; Mather, Karen A; Mathias, Samuel R; McMahon, Katie L; McRae, Allan F; Medland, Sarah E; Moberget, Torgeir; Moreau, Clara; Morris, Derek W; Muhleisen, Thomas W; Murray, Robin M; Nordvik, Jan E; Nyberg, Lars; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Michael J; Paus, Tomas; Pausova, Zdenka; Peralta, Juan M; Pike, Bruce; Prieto, Carlos; Quinlan, Erin Burke; Reinbold, Celine S; Reis Marques, Tiago; Rucker, James J H; Sachdev, Perminder S; Sando, Sigrid B; Schofield, Peter R; Schork, Andrew J; Schumann, Gunter; Shin, Jean; Shumskaya, Elena; Silva, Ana I; Sisodiya, Sanjay M; Steen, Vidar M; Stein, Dan J; Strike, Lachlan T; Tamnes, Christian K; Teumer, Alexander; Thalamuthu, Anbupalam; Tordesillas-Gutierrez, Diana; Uhlmann, Anne; Ulfarsson, Magnus O; van 't Ent, Dennis; van den Bree, Marianne B M; Vassos, Evangelos; Wen, Wei; Wittfeld, Katharina; Wright, Margaret J; Zayats, Tetyana; Dale, Anders M; Djurovic, Srdjan; Agartz, Ingrid; Westlye, Lars T; Stefansson, Hreinn; Stefansson, Kari; Thompson, Paul M; Andreassen, Ole A. [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 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (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. This study is supported in part by grants U54 EB20403, R01MH116147, and R56AG058854 from the National Institutes of Health, grant 609020 from the European Union Seventh Framework Programme, and grants 223273 and 276082 from the Research Council Norway. Part of this work was performed using the Service for Sensitive Data (TSD), which is developed and operated by the TSD Service Groupand owned by the University of Oslo. |
author2 |
National Institutes of Health (US) European Commission Research Council of Norway University of Oslo |
format |
Article in Journal/Newspaper |
author |
van der Meer, Dennis Crespo-Facorro, Benedicto Andreassen, Ole A. ENIGMA-CNV Working Group |
spellingShingle |
van der Meer, Dennis Crespo-Facorro, Benedicto Andreassen, Ole A. ENIGMA-CNV Working Group Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition |
author_facet |
van der Meer, Dennis Crespo-Facorro, Benedicto Andreassen, Ole A. ENIGMA-CNV Working Group |
author_sort |
van der Meer, Dennis |
title |
Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition |
title_short |
Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition |
title_full |
Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition |
title_fullStr |
Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition |
title_full_unstemmed |
Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition |
title_sort |
association of copy number variation of the 15q11.2 bp1-bp2 region with cortical and subcortical morphology and cognition |
publisher |
American Medical Association |
publishDate |
2020 |
url |
http://hdl.handle.net/10261/236107 https://doi.org/10.1001/jamapsychiatry.2019.3779 |
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Andreassen Blackburn Bree Christiane Gunter Ida Kari Knowles McMahon Norway Peralta Prieto Schumann Sigrid Steen Stefansson Sven |
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info:eu-repo/grantAgreement/EC/FP7/223273 info:eu-repo/grantAgreement/EC/FP7/276082 http://doi.org/10.1001/jamapsychiatry.2019.3779 Sí doi:10.1001/jamapsychiatry.2019.3779 issn: 2168-622X e-issn: 2168-6238 JAMA Psychiatry 77: 420 (2020) http://hdl.handle.net/10261/236107 |
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ftcsic:oai:digital.csic.es:10261/236107 2023-05-15T16:53:25+02:00 Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition van der Meer, Dennis Crespo-Facorro, Benedicto Andreassen, Ole A. ENIGMA-CNV Working Group National Institutes of Health (US) European Commission Research Council of Norway University of Oslo 2020 http://hdl.handle.net/10261/236107 https://doi.org/10.1001/jamapsychiatry.2019.3779 eng eng American Medical Association info:eu-repo/grantAgreement/EC/FP7/223273 info:eu-repo/grantAgreement/EC/FP7/276082 http://doi.org/10.1001/jamapsychiatry.2019.3779 Sí doi:10.1001/jamapsychiatry.2019.3779 issn: 2168-622X e-issn: 2168-6238 JAMA Psychiatry 77: 420 (2020) http://hdl.handle.net/10261/236107 closedAccess artículo 2020 ftcsic https://doi.org/10.1001/jamapsychiatry.2019.3779 2021-03-30T23:33:19Z ENIGMA-CNV Working Group: van der Meer, Dennis; Sonderby, Ida E; Kaufmann, Tobias; Walters, G Bragi; Abdellaoui, Abdel; Ames, David; Amunts, Katrin; Andersson, Micael; Armstrong, Nicola J; Bernard, Manon; Blackburn, Nicholas B; Blangero, John; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Bulow, Robin; Cahn, Wiepke; Calhoun, Vince D; Caspers, Svenja; Cavalleri, Gianpiero L; Ching, Christopher R K; Cichon, Sven; Ciufolini, Simone; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Dalvie, Shareefa; Dazzan, Paola; de Geus, Eco J C; de Zubicaray, Greig I; de Zwarte, Sonja M C; Delanty, Norman; den Braber, Anouk; Desrivieres, Sylvane; Di Forti, Marta; Doherty, Joanne L; Donohoe, Gary; Ehrlich, Stefan; Eising, Else; Espeseth, Thomas; Fisher, Simon E; Fladby, Tormod; Frei, Oleksandr; Frouin, Vincent; Fukunaga, Masaki; Gareau, Thomas; Glahn, David C; Grabe, Hans J; Groenewold, Nynke A; Gustafsson, Omar; Haavik, Jan; Haberg, Asta K; Hashimoto, Ryota; Hehir-Kwa, Jayne Y; Hibar, Derrek P; Hillegers, Manon H J; Hoffmann, Per; Holleran, Laurena; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Jacquemont, Sebastien; Jahanshad, Neda; Jockwitz, Christiane; Johansson, Stefan; Jonsson, Erik G; Kikuchi, Masataka; Knowles, Emma E M; Kwok, John B; Le Hellard, Stephanie; Linden, David E J; Liu, Jingyu; Lundervold, Arvid; Lundervold, Astri J; Martin, Nicholas G; Mather, Karen A; Mathias, Samuel R; McMahon, Katie L; McRae, Allan F; Medland, Sarah E; Moberget, Torgeir; Moreau, Clara; Morris, Derek W; Muhleisen, Thomas W; Murray, Robin M; Nordvik, Jan E; Nyberg, Lars; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Michael J; Paus, Tomas; Pausova, Zdenka; Peralta, Juan M; Pike, Bruce; Prieto, Carlos; Quinlan, Erin Burke; Reinbold, Celine S; Reis Marques, Tiago; Rucker, James J H; Sachdev, Perminder S; Sando, Sigrid B; Schofield, Peter R; Schork, Andrew J; Schumann, Gunter; Shin, Jean; Shumskaya, Elena; Silva, Ana I; Sisodiya, Sanjay M; Steen, Vidar M; Stein, Dan J; Strike, Lachlan T; Tamnes, Christian K; Teumer, Alexander; Thalamuthu, Anbupalam; Tordesillas-Gutierrez, Diana; Uhlmann, Anne; Ulfarsson, Magnus O; van 't Ent, Dennis; van den Bree, Marianne B M; Vassos, Evangelos; Wen, Wei; Wittfeld, Katharina; Wright, Margaret J; Zayats, Tetyana; Dale, Anders M; Djurovic, Srdjan; Agartz, Ingrid; Westlye, Lars T; Stefansson, Hreinn; Stefansson, Kari; Thompson, Paul M; Andreassen, Ole A. [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 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (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. This study is supported in part by grants U54 EB20403, R01MH116147, and R56AG058854 from the National Institutes of Health, grant 609020 from the European Union Seventh Framework Programme, and grants 223273 and 276082 from the Research Council Norway. Part of this work was performed using the Service for Sensitive Data (TSD), which is developed and operated by the TSD Service Groupand owned by the University of Oslo. Article in Journal/Newspaper Iceland Digital.CSIC (Spanish National Research Council) Andreassen ENVELOPE(-57.769,-57.769,-63.899,-63.899) Blackburn ENVELOPE(-147.267,-147.267,-86.283,-86.283) Bree ENVELOPE(9.466,9.466,62.617,62.617) Christiane ENVELOPE(70.233,70.233,-49.350,-49.350) Gunter ENVELOPE(-66.511,-66.511,-68.993,-68.993) Ida ENVELOPE(170.483,170.483,-83.583,-83.583) Kari ENVELOPE(28.979,28.979,66.201,66.201) Knowles ENVELOPE(-60.883,-60.883,-71.800,-71.800) McMahon ENVELOPE(65.148,65.148,-70.835,-70.835) Norway Peralta ENVELOPE(-44.817,-44.817,-60.733,-60.733) Prieto ENVELOPE(-62.000,-62.000,-64.683,-64.683) Schumann ENVELOPE(-73.691,-73.691,-71.641,-71.641) Sigrid ENVELOPE(-64.233,-64.233,-64.250,-64.250) Steen ENVELOPE(7.780,7.780,62.571,62.571) Stefansson ENVELOPE(-62.417,-62.417,-69.467,-69.467) Sven ENVELOPE(-60.200,-60.200,-63.733,-63.733) JAMA Psychiatry 77 4 420 |