TY - JOUR
T1 - Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes
AU - Lionel, Anath C.
AU - Tammimies, Kristiina
AU - Vaags, Andrea K.
AU - Rosenfeld, Jill A.
AU - Ahn, Joo Wook
AU - Merico, Daniele
AU - Noor, Abdul
AU - Runke, Cassandra K.
AU - Pillalamarri, Vamsee K.
AU - Carter, Melissa T.
AU - Gazzellone, Matthew J.
AU - Thiruvahindrapuram, Bhooma
AU - Fagerberg, Christina
AU - Laulund, Lone W.
AU - Pellecchia, Giovanna
AU - Lamoureux, Sylvia
AU - Deshpande, Charu
AU - Clayton-Smith, Jill
AU - White, Ann C.
AU - Leather, Susan
AU - Trounce, John
AU - Bedford, H. Melanie
AU - Hatchwell, Eli
AU - Eis, Peggy S.
AU - Yuen, Ryan K.C.
AU - Walker, Susan
AU - Uddin, Mohammed
AU - Geraghty, Michael T.
AU - Nikkel, Sarah M.
AU - Tomiak, Eva M.
AU - Fernandez, Bridget A.
AU - Soreni, Noam
AU - Crosbie, Jennifer
AU - Arnold, Paul D.
AU - Schachar, Russell J.
AU - Roberts, Wendy
AU - Paterson, Andrew D.
AU - So, Joyce
AU - Szatmari, Peter
AU - Chrysler, Christina
AU - Woodbury-Smith, Marc
AU - Lowry, R. Brian
AU - Zwaigenbaum, Lonnie
AU - Mandyam, Divya
AU - Wei, John
AU - MacDonald, Jeffrey R.
AU - Howe, Jennifer L.
AU - Nalpathamkalam, Thomas
AU - Wang, Zhuozhi
AU - Tolson, Daniel
AU - Cobb, David S.
AU - Wilks, Timothy M.
AU - Sorensen, Mark J.
AU - Bader, Patricia I.
AU - An, Yu
AU - Wu, Bai Lin
AU - Musumeci, Sebastiano Antonino
AU - Romano, Corrado
AU - Postorivo, Diana
AU - Nardone, Anna M.
AU - Monica, Matteo Della
AU - Scarano, Gioacchino
AU - Zoccante, Leonardo
AU - Novara, Francesca
AU - Zuffardi, Orsetta
AU - Ciccone, Roberto
AU - Antona, Vincenzo
AU - Carella, Massimo
AU - Zelante, Leopoldo
AU - Cavalli, Pietro
AU - Poggiani, Carlo
AU - Cavallari, Ugo
AU - Argiropoulos, Bob
AU - Chernos, Judy
AU - Brasch-Andersen, Charlotte
AU - Speevak, Marsha
AU - Fichera, Marco
AU - Ogilvie, Caroline Mackie
AU - Shen, Yiping
AU - Hodge, Jennelle C.
AU - Talkowski, Michael E.
AU - Stavropoulos, Dimitri J.
AU - Marshall, Christian R.
AU - Scherer, Stephen W.
N1 - Funding Information:
This work was supported by grants from the University of Toronto McLaughlin Centre, NeuroDevNet, Genome Canada and the Ontario Genomics Institute, the Canadian Institutes for Health Research (CIHR), National Institutes of Health (MH095867), the Canadian Institute for Advanced Research, the Canada Foundation for Innovation, the Government of Ontario, Autism Speaks and The Hospital for Sick Children Foundation. A.C.L. was supported by a NeuroDevNet doctoral fellowship. K.T. holds a postdoctoral fellowship from the Swedish Research Council. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. D.T., D.S.C. and T.M.W. are US military service members and this work was prepared as part of their official duties. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army, Department of the Navy, Department of Defense, nor the US Government. Title 17, USC § 105 provides that ‘Copyright protection under this title is not available for any work of the U.S. Government.’ Title 17, USC § 101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties. Control datasets were obtained, along with permission for use, from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through accession numbers phs000143.v1.p1 (Starr County Health Studies’ Genetics of Diabetes Study), phs000091.v2.p1 (GENEVA NHS/HPFS Diabetes study), phs000169.v1.p1 (Whole Genome Association Study of Visceral Adiposity in the HABC Study), phs000303.v1.p1 (Genetic Epidemiology of Refractive Error in the KORA Study), phs000404.v1.p1 (COGEND; The Genetic Architecture of Smoking and Smoking Cessation) and phs000086.v2.p1 (DCCT-EDIC Clinical Trial and Follow-up of Persons with Type 1 Diabetes). The Starr County Health Studies Genetics of Diabetes Study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NIDDK Central Repositories. Support for the GWAS of Gene and Environment Initiatives in Type 2 Diabetes was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01HG004399). The human subjects participating in the GWAS derive from The Nurses’ Health Study and Health Professionals’ Follow-up Study and these studies are supported by National Institutes of Health (NIH) grants CA87969, CA55075 and DK58845. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies, GENEVA Coordinating Center (U01 HG004446) and the National Center for Biotechnology Information. Support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH GEI (U01HG004424). Support for the ‘CIDR Visceral Adiposity Study’ was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, National Institute on Aging. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Health ABC Study (HABC) Investigators. The KORA dataset was obtained from the NEI Refractive Error Collaboration (NEIREC) Database, support for which was provided by the National Eye Institute. Support for genotyping of the COGEND samples, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. Assistance with genotype cleaning of the COGEND samples, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01HG004446). Support for the collection of COGEND datasets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). The DCCT-EDIC Research Group is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the NIDDK and the NIH. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIDDK or the NIH.
PY - 2014/5
Y1 - 2014/5
N2 - Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
AB - Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
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U2 - 10.1093/hmg/ddt669
DO - 10.1093/hmg/ddt669
M3 - Article
C2 - 24381304
AN - SCOPUS:84898772564
VL - 23
SP - 2752
EP - 2768
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 10
M1 - ddt669
ER -