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1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway.
NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands.
Sainte Justine Hospital Research Center, QC, Montreal, Canada; Centre de recherche de l'Institut universitaire de gériatrie de Montréal, QC, Montreal, Canada.
NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
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2021 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 182Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021. Vol. 11, no 1, article id 182
National Category
Psychiatry Medical Genetics and Genomics
Identifiers
URN: urn:nbn:se:umu:diva-186321DOI: 10.1038/s41398-021-01213-0ISI: 000632961500003PubMedID: 33753722Scopus ID: 2-s2.0-85101254052OAI: oai:DiVA.org:umu-186321DiVA, id: diva2:1581478
Funder
EU, Horizon 2020, 945539, 695313, PR-ST-0416-10004, MR/N027558/1, 785907Swedish Research Council, 2018-05973, K2010-62X-15078-07-2, K2012-61X-15078-09-3, 521-2014-3487, K2015-62X-15077-12-3, 2017-00949EU, FP7, Seventh Framework Programme, 602450, 609020Wellcome trustNIH (National Institute of Health), U54 EB20403, R01MH116147, R56AG058854, C06 RR020547, 5T32MH073526, R01 MH078143, R01 MH078111, R01 MH083824, R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, R01 DK092127-04, 1RC2 MH089951, 1RC2 MH089995, R01EB006841, P20GM103472, P30GM122734, U54 EB020403, RC2DA029475, R01 HD050735Region StockholmSwedish Research CouncilSwedish Research Council FormasAvailable from: 2021-07-21 Created: 2021-07-21 Last updated: 2025-02-10Bibliographically approved

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Andersson, MicaelNyberg, Lars

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