Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

By Joseph Glessner, Kai Wang, Guiqing Cai, Olena Korvatska, Cecilia Kim, Shawn Wood, Haitao Zhang, Annette M. Estes, Camille W. Brune, J. Bradfield and 49 more. Nature, 2009

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Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ∼550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10-3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10-6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

Subfields: Cognitive Neuroscience, Genetics

View Paper: https://www.semanticscholar.org/paper/47e502d3f677b9995f2c4909dc5c0f6455ae3db2

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Citations in the corpus

Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities and core autism-related deficits (2011, neutral): “Research into the genetic basis for ASD has identified many genes, including common and rare variants (Sebat et al., 2007; Glessner et al., 2009; Weiss et al., 2009).”
The Philadelphia Neurodevelopmental Cohort: A Publicly Available Resource for the Study of Normal and Abnormal Brain Development in Youth (2015, neutral): “Genotyping procedures are not discussed here, but the genotyping pipeline used at CAG has been previously described in detail (Pinto et al., 2010; Glessner et al., 2009) and further information can be accessed at www.”
Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. (2011, background): “…revealed submicroscopic deletions and duplications, called copy number variation (CNV), affecting many loci and including de novo events in 5%–10% of ASD cases (Christian et al., 2008; Glessner et al., 2009; Marshall et al., 2008; Pinto et al., 2010; Sebat et al., 2007; Szatmari et al., 2007).”
Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia (2016, background): “It plays a key role in olfactory axon guidance (41), and 274 there is evidence for association of copy number variants overlapping CNTN4 with autism (42).”
The Angelman Syndrome-associated ubiquitin ligase Ube3A regulates synapse development by ubiquitinating Arc (2010, neutral): “Furthermore, recent reports indicate that copy number variance specifically within the Ube3A locus is associated with autism (Glessner et al., 2009).”
Modelling learning and memory in Drosophila to understand Intellectual Disabilities. (2020, neutral): “Furthermore, CNVs for several neuroligin genes have been reported in ASDs and SCZ cohorts (Laumonnier et al., 2004; Blasi et al., 2006; Glessner et al., 2009; Sun et al., 2011a; Parente et al., 2017).”