Dataset Information

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

ABSTRACT: 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.

SUBMITTER: Sonderby IE

PROVIDER: S-EPMC7985307 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Sønderby Ida E IE van der Meer Dennis D Moreau Clara C Kaufmann Tobias T Walters G Bragi GB Ellegaard Maria M Abdellaoui Abdel A Ames David D Amunts Katrin K Andersson Micael M Armstrong Nicola J NJ Bernard Manon M Blackburn Nicholas B NB Blangero John J Boomsma Dorret I DI Brodaty Henry H Brouwer Rachel M RM Bülow Robin R Bøen Rune R Cahn Wiepke W Calhoun Vince D VD Caspers Svenja S Ching Christopher R K CRK Cichon Sven S Ciufolini Simone S Crespo-Facorro Benedicto B Curran Joanne E JE Dale Anders M AM Dalvie Shareefa S Dazzan Paola P de Geus Eco J C EJC de Zubicaray Greig I GI de Zwarte Sonja M C SMC Desrivieres Sylvane S Doherty Joanne L JL Donohoe Gary G Draganski Bogdan B Ehrlich Stefan S Eising Else E Espeseth Thomas T Fejgin Kim K Fisher Simon E SE Fladby Tormod T Frei Oleksandr O Frouin Vincent V Fukunaga Masaki M Gareau Thomas T Ge Tian T Glahn David C DC Grabe Hans J HJ Groenewold Nynke A NA Gústafsson Ómar Ó Haavik Jan J Haberg Asta K AK Hall Jeremy J Hashimoto Ryota R Hehir-Kwa Jayne Y JY Hibar Derrek P DP Hillegers Manon H J MHJ Hoffmann Per P Holleran Laurena L Holmes Avram J AJ Homuth Georg G Hottenga Jouke-Jan JJ Hulshoff Pol Hilleke E HE Ikeda Masashi M Jahanshad Neda N Jockwitz Christiane C Johansson Stefan S Jönsson Erik G EG Jørgensen Niklas R NR Kikuchi Masataka M Knowles Emma E M EEM Kumar Kuldeep K Le Hellard Stephanie S Leu Costin C Linden David E J DEJ Liu Jingyu J Lundervold Arvid A Lundervold Astri Johansen AJ Maillard Anne M AM Martin Nicholas G NG Martin-Brevet Sandra S Mather Karen A KA Mathias Samuel R SR McMahon Katie L KL McRae Allan F AF Medland Sarah E SE Meyer-Lindenberg Andreas A Moberget Torgeir T Modenato Claudia C Sánchez Jennifer Monereo JM Morris Derek W DW Mühleisen Thomas W TW Murray Robin M RM Nielsen Jacob J Nordvik Jan E JE Nyberg Lars L Loohuis Loes M Olde LMO Ophoff Roel A RA Owen Michael J MJ Paus Tomas T Pausova Zdenka Z Peralta Juan M JM Pike G Bruce GB Prieto Carlos C Quinlan Erin B EB Reinbold Céline S CS Marques Tiago Reis TR Rucker James J H JJH Sachdev Perminder S PS Sando Sigrid B SB Schofield Peter R PR Schork Andrew J AJ Schumann Gunter G Schumann Gunter G Shin Jean J Shumskaya Elena E Silva Ana I AI Sisodiya Sanjay M SM Steen Vidar M VM Stein Dan J DJ Strike Lachlan T LT Suzuki Ikuo K IK Tamnes Christian K CK Teumer Alexander A Thalamuthu Anbupalam A Tordesillas-Gutiérrez Diana D Uhlmann Anne A Ulfarsson Magnus O MO van 't Ent Dennis D van den Bree Marianne B M MBM Vanderhaeghen Pierre P Vassos Evangelos E Wen Wei W Wittfeld Katharina K Wright Margaret J MJ Agartz Ingrid I Djurovic Srdjan S Westlye Lars T LT Stefansson Hreinn H Stefansson Kari K Jacquemont Sébastien S Thompson Paul M PM Andreassen Ole A OA

Translational psychiatry 20210322 1

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 Bioba ...[more]

PMID: 33753722

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Project description:BACKGROUND:1q21.1 Copy Number Variant (CNV) is associated with a highly variable phenotype ranging from congenital anomalies, learning deficits/intellectual disability (ID), to a normal phenotype. Hence, the clinical significance of this CNV can be difficult to evaluate. Here we described the consequences of the 1q21.1 CNV on genome-wide gene expression and function of selected candidate genes within 1q21.1 using cell lines from clinically well described subjects. METHODS AND RESULTS:Eight subjects from 3 families were included in the study: six with a 1q21.1 deletion and two with a 1q21.1 duplication. High resolution Affymetrix 2.7M array was used to refine the 1q21.1 CNV breakpoints and exclude the presence of secondary CNVs of pathogenic relevance. Whole genome expression profiling, studied in lymphoblast cell lines (LBCs) from 5 subjects, showed enrichment of genes from 1q21.1 in the top 100 genes ranked based on correlation of expression with 1q21.1 copy number. The function of two top genes from 1q21.1, CHD1L/ALC1 and PRKAB2, was studied in detail in LBCs from a deletion and a duplication carrier. CHD1L/ALC1 is an enzyme with a role in chromatin modification and DNA damage response while PRKAB2 is a member of the AMP kinase complex, which senses and maintains systemic and cellular energy balance. The protein levels for CHD1L/ALC1 and PRKAB2 were changed in concordance with their copy number in both LBCs. A defect in chromatin remodeling was documented based on impaired decatenation (chromatid untangling) checkpoint (DCC) in both LBCs. This defect, reproduced by CHD1L/ALC1 siRNA, identifies a new role of CHD1L/ALC1 in DCC. Both LBCs also showed elevated levels of micronuclei following treatment with a Topoisomerase II inhibitor suggesting increased DNA breaks. AMP kinase function, specifically in the deletion containing LBCs, was attenuated. CONCLUSION:Our studies are unique as they show for the first time that the 1q21.1 CNV not only causes changes in the expression of its key integral genes, associated with changes at the protein level, but also results in changes in their known function, in the case of AMPK, and newly identified function such as DCC activation in the case of CHD1L/ALC1. Our results support the use of patient lymphoblasts for dissecting the functional sequelae of genes integral to CNVs in carrier cell lines, ultimately enhancing understanding of biological processes which may contribute to the clinical phenotype.

Project description:ObjectivesCopy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs) including autism (ASD) and schizophrenia (SZ). Overall, little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, we investigated gross volume, and vertex level thickness and surface maps of subcortical structures in 11 different CNVs and 6 different NPDs.MethodsSubcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (at the following loci: 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2) and 782 controls (Male/Female: 727/730; age-range: 6-80 years) as well as ENIGMA summary-statistics for ASD, SZ, ADHD, Obsessive-Compulsive-Disorder, Bipolar-Disorder, and Major-Depression.ResultsNine of the 11 CNVs affected volume of at least one subcortical structure. The hippocampus and amygdala were affected by five CNVs. Effect sizes of CNVs on subcortical volume, thickness and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and SZ. Shape analyses were able to identify subregional alterations that were averaged out in volume analyses. We identified a common latent dimension - characterized by opposing effects on basal ganglia and limbic structures - across CNVs and across NPDs.ConclusionOur findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions. We also observed distinct effects with some CNVs clustering with adult conditions while others clustered with ASD. This large cross-CNV and NPDs analysis provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD, as well as why a single CNV increases the risk for a diverse set of NPDs.

Project description:ObjectiveCopy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs), including autism (ASD) and schizophrenia. Little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, the authors investigated gross volume, vertex-level thickness, and surface maps of subcortical structures in 11 CNVs and six NPDs.MethodsSubcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (CNVs at 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2; age range, 6-80 years; 340 males) and 782 control subjects (age range, 6-80 years; 387 males) as well as ENIGMA summary statistics for ASD, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, bipolar disorder, and major depression.ResultsAll CNVs showed alterations in at least one subcortical measure. Each structure was affected by at least two CNVs, and the hippocampus and amygdala were affected by five. Shape analyses detected subregional alterations that were averaged out in volume analyses. A common latent dimension was identified, characterized by opposing effects on the hippocampus/amygdala and putamen/pallidum, across CNVs and across NPDs. Effect sizes of CNVs on subcortical volume, thickness, and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and schizophrenia.ConclusionsThe findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions, as well distinct effects, with some CNVs clustering with adult-onset conditions and others with ASD. These findings provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD and why a single CNV increases the risk for a diverse set of NPDs.

Dataset Information

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Publications

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

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