Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways

• Published in: Human molecular genetics Vol. 21; no. 15; pp. 3513 - 3523
• Main Authors: Griswold, Anthony J., Ma, Deqiong, Cukier, Holly N., Nations, Laura D., Schmidt, Mike A., Chung, Ren-Hua, Jaworski, James M., Salyakina, Daria, Konidari, Ioanna, Whitehead, Patrice L., Wright, Harry H., Abramson, Ruth K., Williams, Scott M., Menon, Ramkumar, Martin, Eden R., Haines, Jonathan L., Gilbert, John R., Cuccaro, Michael L., Pericak-Vance, Margaret A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.08.2012
• Subjects: Adolescent; Algorithms; Allosteric properties; Association Studies; Autism; Biological and medical sciences; Case-Control Studies; Cerebellum; Child; Child clinical studies; Child Development Disorders, Pervasive - genetics; Child, Preschool; copy number; Data processing; Developmental disorders; DNA Copy Number Variations; Female; Fundamental and applied biological sciences. Psychology; GABARAP protein; gamma -Aminobutyric acid; gamma -Aminobutyric acid receptors; gamma -Aminobutyric acid transporter; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Glutamic acid receptors; Heritability; Humans; Infantile autism; Male; Medical sciences; Mental disorders; Molecular and cellular biology; Morphogenesis; Notch protein; Polymorphism, Single Nucleotide; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, GABA - genetics; RNA-binding protein; Signal transduction; Single-nucleotide polymorphism; Transcription factors; Young Adult; Autism; Genetics; Pervasive developmental disorder; Developmental disorder; Candidate gene; Copy number variation
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/dds164

Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to <1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry case-control data set. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, 18 deletions larger than 1 Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12 and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include DBI, an allosteric binder of GABA receptors, GABARAPL1, the GABA receptor-associated protein, and SLC6A11, a postsynaptic GABA transporter. We also identified CNVs in COBL, deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and DNER, a neuron-specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors (GRID1, GRIK2 and GRIK4), synaptic regulators (NRXN3, SLC6A8 and SYN3), transcription factor (ZNF804A) and RNA-binding protein FMR1. Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms.