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

Anthony J. Griswold, Deqiong Ma, Holly N. Cukier, Laura D. Nations, Mike A. Schmidt, Ren Hua Chung, James M. Jaworski, Daria Salyakina, Ioanna Konidari, Patrice L. Whitehead, Harry H. Wright, Ruth K. Abramson, Scott M. Williams, Ramkumar Menon, Eden R. Martin, Jonathan L. Haines, John R. Gilbert, Michael L. Cuccaro, Margaret A. Pericak-Vance

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


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.

Original languageEnglish (US)
Article numberdds164
Pages (from-to)3513-3523
Number of pages11
JournalHuman Molecular Genetics
Issue number15
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways'. Together they form a unique fingerprint.

Cite this