van der Meer, D and Sonderby, IE and Kaufmann, T and Walters, GB and Abdellaoui, A and Ames, D and Amunts, K and Andersson, M and Armstrong, NJ and Bernard, M and Blackburn, NB and Blangero, J and Boomsma, DI and Brodaty, H and Brouwer, RM and Bulow, R and Cahn, W and Calhoun, VD and Caspers, S and Cavalleri, GL and Ching, CRK and Cichon, S and Ciufolini, S and Corvin, A and Crespo-Facorro, B and Curran, JE and Dalvie, S and Dazzan, P and de Geus, EJC and de Zubicaray, GI and de Zwarte, SMC and Delanty, N and den Braber, A and Desrivieres, S and Di Forti, M and Doherty, JL and Donohoe, G and Ehrlich, S and Eising, E and Espeseth, T and Fisher, SE and Fladby, T and Frei, O and Frouin, V and Fukunaga, M and Gareau, T and Glahn, DC and Grabe, HJ and Groenewold, NA and Gustafsson, O and Haavik, J and Haberg, AK and Hashimoto, R and Hehir-Kwa, JY and Hibar, DP and Hillegers, MHJ and Hoffmann, P and Holleran, L and Hottenga, J-J and Hulshoff Pol, HE and Ikeda, M and Jacquemont, S and Jahanshad, N and Jockwitz, C and Johansson, S and Jonsson, EG and Kikuchi, M and Knowles, EEM and Kwok, JB and Le Hellard, S and Linden, DEJ and Liu, J and Lundervold, A and Lundervold, AJ and Martin, NG and Mather, KA and Mathias, SR and McMahon, KL and McRae, AF and Medland, SE and Moberget, T and Moreau, C and Morris, DW and Muhleisen, TW and Murray, RM and Nordvik, JE and Nyberg, L and Loohuis, LMO and Ophoff, RA and Owen, MJ and Paus, T and Pausova, Z and Peralta, JM and Pike, B and Prieto, C and Burke Quinlan, E and Reinbold, CS and Marques, TR and Rucker, JJH and Sachdev, PS and Sando, SB and Schofield, PR and Silva, AI and Sisodiya, SM and Steen, VM and Stein, DJ and Strike, LT and Tamnes, CK and Teumer, A and Thalamuthu, A and Tordesillas-Gutierrez, D and Uhlmann, A and Ulfarsson, MO and van 't Ent, D and van den Bree, MBM and Vassos, E and Wen, W and Wittfeld, K and Wright, MJ and Zayats, T and Dale, AM and Djurovic, S and Agartz, I and Westlye, LT and Stefansson, H and Stefansson, K and Thompson, PM and Andreassen, OA, Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition, JAMA Psychiatry, 77, (4) pp. 420-430. ISSN 2168-622X (2020) [Refereed Article]
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.
|Item Type:||Refereed Article|
|Keywords:||brain morphology, copy number variation|
|Research Division:||Biological Sciences|
|Objective Division:||Expanding Knowledge|
|Objective Group:||Expanding knowledge|
|Objective Field:||Expanding knowledge in the biomedical and clinical sciences|
|UTAS Author:||Blackburn, NB (Dr Nicholas Blackburn)|
|Web of Science® Times Cited:||18|
|Deposited By:||Menzies Institute for Medical Research|
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