Dataset Information

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

ABSTRACT: 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 (??=?-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.

SUBMITTER: Writing Committee for the ENIGMA-CNV Working Group

PROVIDER: S-EPMC6822096 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

van der Meer Dennis D Sønderby Ida E IE Kaufmann Tobias T Walters G Bragi GB 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 Cahn Wiepke W Calhoun Vince D VD Caspers Svenja S Cavalleri Gianpiero L GL Ching Christopher R K CRK Cichon Sven S Ciufolini Simone S Corvin Aiden A Crespo-Facorro Benedicto B Curran Joanne E JE Dalvie Shareefa S Dazzan Paola P de Geus Eco J C EJC de Zubicaray Greig I GI de Zwarte Sonja M C SMC Delanty Norman N den Braber Anouk A Desrivieres Sylvane S Di Forti Marta M Doherty Joanne L JL Donohoe Gary G Ehrlich Stefan S Eising Else E Espeseth Thomas T Fisher Simon E SE Fladby Tormod T Frei Oleksandr O Frouin Vincent V Fukunaga Masaki M Gareau Thomas T Glahn David C DC Grabe Hans J HJ Groenewold Nynke A NA Gústafsson Ómar Ó Haavik Jan J Haberg Asta K AK Hashimoto Ryota R Hehir-Kwa Jayne Y JY Hibar Derrek P DP Hillegers Manon H J MHJ Hoffmann Per P Holleran Laurena L Hottenga Jouke-Jan JJ Hulshoff Pol Hilleke E HE Ikeda Masashi M Jacquemont Sébastien S Jahanshad Neda N Jockwitz Christiane C Johansson Stefan S Jönsson Erik G EG Kikuchi Masataka M Knowles Emma E M EEM Kwok John B JB Le Hellard Stephanie S Linden David E J DEJ Liu Jingyu J Lundervold Arvid A Lundervold Astri J AJ Martin Nicholas G NG Mather Karen A KA Mathias Samuel R SR McMahon Katie L KL McRae Allan F AF Medland Sarah E SE Moberget Torgeir T Moreau Clara C Morris Derek W DW Mühleisen Thomas W TW Murray Robin M RM Nordvik Jan E JE Nyberg Lars L Olde Loohuis Loes M LM Ophoff Roel A RA Owen Michael J MJ Paus Tomas T Pausova Zdenka Z Peralta Juan M JM Pike Bruce B Prieto Carlos C Quinlan Erin Burke EB Reinbold Céline S CS Reis Marques Tiago T Rucker James J H JJH Sachdev Perminder S PS Sando Sigrid B SB Schofield Peter R PR Schork Andrew J AJ 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 Tamnes Christian K CK Teumer Alexander A Thalamuthu Anbupalam A Tordesillas-Gutiérrez Diana D Uhlmann Anne A Úlfarsson Magnús Ö MÖ van 't Ent Dennis D van den Bree Marianne B M MBM Vassos Evangelos E Wen Wei W Wittfeld Katharina K Wright Margaret J MJ Zayats Tetyana T Dale Anders M AM Djurovic Srdjan S Agartz Ingrid I Westlye Lars T LT Stefánsson Hreinn H Stefánsson Kári K Thompson Paul M PM Andreassen Ole A OA

JAMA psychiatry 20200401 4

<h4>Importance</h4>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.<h4>Objective</h4>To determine the association of ...[more]

PMID: 31665216

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Project description:BackgroundSeveral copy number variations (CNVs) are associated with increased risk for neurodevelopmental and psychiatric disorders. The CNV 15q11.2 (BP1-BP2) deletion has been associated with learning difficulties, attention deficit hyperactivity disorder (ADHD), epilepsy, and brain morphology; however, many carriers present mild or no symptoms. Carrying the reciprocal duplication does not seem to confer risk for these disorders or traits. Our aim was to examine the impact of carrying either 15q11.2 deletion and reciprocal duplication on neurodevelopmental problems in a population-based sample of children.MethodsTwins with genotype and phenotype information in the Child and Adolescent Twin Study in Sweden (CATSS) were included (N = 12,040). We included measures of neurodevelopmental problems (NDPs), including learning problems, from the questionnaire Autism-Tics, ADHD, and other Comorbidities inventory (A-TAC) at age 9/12, ADHD and autism spectrum disorder (ASD) questionnaires at age 18, as well as information about lifetime psychiatric diagnoses and epileptic seizures. We tested the association between these phenotypic measurements and carrying the 15q11.2 deletion, the reciprocal duplication, and other CNVs with previously reported strong associations with neurodevelopmental and psychiatric disorders (i.e., psychiatric CNVs).ResultsWe identified 57 carriers of the 15q11.2 deletion, 75 carriers of the reciprocal duplication, and 67 carriers of other psychiatric CNVs. We did not find an increased risk for NDPs or psychiatric diagnoses in the 15q11.2 deletion carriers. For 15q11.2 duplication carriers, we found an increased risk for math learning problems and fewer self-reported ADHD symptoms at age 18 but not for other NDPs. In line with previous studies, we found an increased risk of NDPs and other evaluated phenotypes in carriers of psychiatric CNVs.ConclusionsOur results support previous findings that carrying 15q11.2 deletion does not have a large effect on NDPs in children.

Project description:The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.

Dataset Information

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

Publications

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

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