Article

Linkage, Association, and Gene-Expression Analyses Identify CNTNAP2 as an Autism-Susceptibility Gene

UCLA Center for Autism Research and Treatment, Semel Institute of Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 02/2008; 82(1):150-9. DOI: 10.1016/j.ajhg.2007.09.005
Source: PubMed

ABSTRACT Autism is a genetically complex neurodevelopmental syndrome in which language deficits are a core feature. We describe results from two complimentary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism. A two-stage association study tested 2758 SNPs across a 10 Mb 7q35 language-related autism QTL in AGRE (Autism Genetic Resource Exchange) trios and found significant association with Contactin Associated Protein-Like 2 (CNTNAP2), a strong a priori candidate. Male-only containing families were identified as primarily responsible for this association signal, consistent with the strong male affection bias in ASD and other language-based disorders. Gene-expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provide convergent evidence for involvement of CNTNAP2, a Neurexin family member, in autism, and demonstrate a connection between genetic risk for autism and specific brain structures.

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Available from: Maricela Alarcón, Aug 22, 2015
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    • "th Runx2 and Foxp2 are found among Auts2 regulatory targets ( Oksenberg et al . , 2014 ) , as is Cntnap2 . CNTNAP2 is a well - known FOXP2 target ( Vernes et al . , 2008 ) and a candidate for language delay and language impairment ( Petrin et al . , 2010 ; Sehested et al . , 2010 ) , intellectual disability ( Gregor et al . , 2011 ) , and autism ( Alarcón et al . , 2008 ; Bakkaloglu et al . , 2008 ) , The AMH CNTNAP2 exhibits a fixed change ( Ile345Val ) compared to the Denisovan protein ( Meyer et al . , 2012 ) . Moreover , CNTNAP2 is related to NFASC , a protein involved in neurite outgrowth and the formation of postsynaptic components ( Kriebel et al . , 2012 ) that shows a fixed change ( T987A ) in"
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    Frontiers in Psychology 06/2015; 6:794. DOI:10.3389/fpsyg.2015.00794 · 2.80 Impact Factor
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    • "The risk allele of CNTNAP2 is closely associated with reduced white matter volume in ASD, and with a reduction of fractal anisotropy in the cerebellum and frontotemporal cortex (Tan et al., 2010). Further, previous studies have reported that rs2710102 of CNTNAP2 is associated with language acquisition in early language development (Whitehouse et al., 2011), or language development disorder (Alarcon et al., 2008; Vernes et al., 2008). Language is processed predominantly in the left hemisphere in most people. "
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    • "Genetics has already informed pharmacological treatment exploration for ASD ( Jeste and Geschwind, 2014). For example , CNTNAP2 variants have been associated with ASD and other neurodevelopmental disorders (Alarcon et al., 2008; Arking et al., 2008); this variant has been shown to have increased expression in frontostriatal circuits of the brain (Abrahams et al., 2007). CNTNAP2-mutant mouse models, which present ASD-like symptoms, have shown alleviated repetitive behaviors, but no change in social deficits when treated with risperidone, a dopamine antagonist (Penagarikano et al., 2011; Penagarikano and Geschwind, 2012). "
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