Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition
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...
Published in: | JAMA Psychiatry |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | unknown |
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American Medical Association
2020
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Online Access: | https://eprints.utas.edu.au/38162/ |
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ftunivtasmania:oai:eprints.utas.edu.au:38162 |
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openpolar |
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Open Polar |
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University of Tasmania: UTas ePrints |
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ftunivtasmania |
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unknown |
topic |
brain morphology copy number variation |
spellingShingle |
brain morphology copy number variation van der Meer, D Sonderby, 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 Bulow, 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 Gustafsson, O Haavik, J Haberg, AK Hashimoto, R Hehir-Kwa, JY Hibar, DP Hillegers, MHJ Hoffmann, P Holleran, L Hottenga, J-J Hulshoff Pol, HE Ikeda, M Jacquemont, S Jahanshad, N Jockwitz, C Johansson, S Jonsson, 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 Muhleisen, TW Murray, RM Nordvik, JE Nyberg, L Loohuis, LMO Ophoff, RA Owen, MJ Paus, T Pausova, Z Peralta, JM Pike, B Prieto, C Burke Quinlan, E Reinbold, CS Marques, TR Rucker, JJH Sachdev, PS Sando, SB Schofield, PR Silva, AI Sisodiya, SM Steen, VM Stein, DJ Strike, LT Tamnes, CK Teumer, A Thalamuthu, A Tordesillas-Gutierrez, D Uhlmann, A Ulfarsson, MO 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 Stefansson, H Stefansson, K Thompson, PM Andreassen, OA Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition |
topic_facet |
brain morphology copy number variation |
description |
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. |
format |
Article in Journal/Newspaper |
author |
van der Meer, D Sonderby, 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 Bulow, 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 Gustafsson, O Haavik, J Haberg, AK Hashimoto, R Hehir-Kwa, JY Hibar, DP Hillegers, MHJ Hoffmann, P Holleran, L Hottenga, J-J Hulshoff Pol, HE Ikeda, M Jacquemont, S Jahanshad, N Jockwitz, C Johansson, S Jonsson, 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 Muhleisen, TW Murray, RM Nordvik, JE Nyberg, L Loohuis, LMO Ophoff, RA Owen, MJ Paus, T Pausova, Z Peralta, JM Pike, B Prieto, C Burke Quinlan, E Reinbold, CS Marques, TR Rucker, JJH Sachdev, PS Sando, SB Schofield, PR Silva, AI Sisodiya, SM Steen, VM Stein, DJ Strike, LT Tamnes, CK Teumer, A Thalamuthu, A Tordesillas-Gutierrez, D Uhlmann, A Ulfarsson, MO 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 Stefansson, H Stefansson, K Thompson, PM Andreassen, OA |
author_facet |
van der Meer, D Sonderby, 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 Bulow, 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 Gustafsson, O Haavik, J Haberg, AK Hashimoto, R Hehir-Kwa, JY Hibar, DP Hillegers, MHJ Hoffmann, P Holleran, L Hottenga, J-J Hulshoff Pol, HE Ikeda, M Jacquemont, S Jahanshad, N Jockwitz, C Johansson, S Jonsson, 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 Muhleisen, TW Murray, RM Nordvik, JE Nyberg, L Loohuis, LMO Ophoff, RA Owen, MJ Paus, T Pausova, Z Peralta, JM Pike, B Prieto, C Burke Quinlan, E Reinbold, CS Marques, TR Rucker, JJH Sachdev, PS Sando, SB Schofield, PR Silva, AI Sisodiya, SM Steen, VM Stein, DJ Strike, LT Tamnes, CK Teumer, A Thalamuthu, A Tordesillas-Gutierrez, D Uhlmann, A Ulfarsson, MO 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 Stefansson, H Stefansson, K Thompson, PM Andreassen, OA |
author_sort |
van der Meer, D |
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 |
https://eprints.utas.edu.au/38162/ |
genre |
Iceland |
genre_facet |
Iceland |
op_relation |
van der Meer, D, Sonderby, IE, Kaufmann, T, Walters, GB, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB orcid:0000-0002-9774-1539 , Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Bulow, 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, Gustafsson, O, Haavik, J, Haberg, AK, Hashimoto, R, Hehir-Kwa, JY, Hibar, DP, Hillegers, MHJ, Hoffmann, P, Holleran, L, Hottenga, J-J, Hulshoff Pol, HE, Ikeda, M, Jacquemont, S, Jahanshad, N, Jockwitz, C, Johansson, S, Jonsson, 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, Muhleisen, TW, Murray, RM, Nordvik, JE, Nyberg, L, Loohuis, LMO, Ophoff, RA, Owen, MJ, Paus, T, Pausova, Z, Peralta, JM, Pike, B, Prieto, C, Burke Quinlan, E, Reinbold, CS, Marques, TR, Rucker, JJH, Sachdev, PS, Sando, SB, Schofield, PR, Silva, AI, Sisodiya, SM, Steen, VM, Stein, DJ, Strike, LT, Tamnes, CK, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Uhlmann, A, Ulfarsson, MO, 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, Stefansson, H, Stefansson, K, Thompson, PM and Andreassen, OA 2020 , '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 , doi:10.1001/jamapsychiatry.2019.3779 <http://dx.doi.org/10.1001/jamapsychiatry.2019.3779>. |
op_doi |
https://doi.org/10.1001/jamapsychiatry.2019.3779 |
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JAMA Psychiatry |
container_volume |
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container_issue |
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container_start_page |
420 |
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ftunivtasmania:oai:eprints.utas.edu.au:38162 2023-05-15T16:53:06+02:00 Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition van der Meer, D Sonderby, 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 Bulow, 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 Gustafsson, O Haavik, J Haberg, AK Hashimoto, R Hehir-Kwa, JY Hibar, DP Hillegers, MHJ Hoffmann, P Holleran, L Hottenga, J-J Hulshoff Pol, HE Ikeda, M Jacquemont, S Jahanshad, N Jockwitz, C Johansson, S Jonsson, 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 Muhleisen, TW Murray, RM Nordvik, JE Nyberg, L Loohuis, LMO Ophoff, RA Owen, MJ Paus, T Pausova, Z Peralta, JM Pike, B Prieto, C Burke Quinlan, E Reinbold, CS Marques, TR Rucker, JJH Sachdev, PS Sando, SB Schofield, PR Silva, AI Sisodiya, SM Steen, VM Stein, DJ Strike, LT Tamnes, CK Teumer, A Thalamuthu, A Tordesillas-Gutierrez, D Uhlmann, A Ulfarsson, MO 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 Stefansson, H Stefansson, K Thompson, PM Andreassen, OA 2020 https://eprints.utas.edu.au/38162/ unknown American Medical Association van der Meer, D, Sonderby, IE, Kaufmann, T, Walters, GB, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB orcid:0000-0002-9774-1539 , Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Bulow, 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, Gustafsson, O, Haavik, J, Haberg, AK, Hashimoto, R, Hehir-Kwa, JY, Hibar, DP, Hillegers, MHJ, Hoffmann, P, Holleran, L, Hottenga, J-J, Hulshoff Pol, HE, Ikeda, M, Jacquemont, S, Jahanshad, N, Jockwitz, C, Johansson, S, Jonsson, 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, Muhleisen, TW, Murray, RM, Nordvik, JE, Nyberg, L, Loohuis, LMO, Ophoff, RA, Owen, MJ, Paus, T, Pausova, Z, Peralta, JM, Pike, B, Prieto, C, Burke Quinlan, E, Reinbold, CS, Marques, TR, Rucker, JJH, Sachdev, PS, Sando, SB, Schofield, PR, Silva, AI, Sisodiya, SM, Steen, VM, Stein, DJ, Strike, LT, Tamnes, CK, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Uhlmann, A, Ulfarsson, MO, 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, Stefansson, H, Stefansson, K, Thompson, PM and Andreassen, OA 2020 , '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 , doi:10.1001/jamapsychiatry.2019.3779 <http://dx.doi.org/10.1001/jamapsychiatry.2019.3779>. brain morphology copy number variation Article PeerReviewed 2020 ftunivtasmania https://doi.org/10.1001/jamapsychiatry.2019.3779 2021-11-01T23:17:55Z 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. Article in Journal/Newspaper Iceland University of Tasmania: UTas ePrints JAMA Psychiatry 77 4 420 |