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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    ABSTRACT: The sequencing of the genomes from extinct hominins has revealed that changes in some brain-related genes have been selected after the split between anatomically-modern humans and Neanderthals/Denisovans. To date, no coherent view of these changes has been provided. Following a line of research we initiated in Boeckx and Benítez-Burraco (2014a), we hypothesize functional links among most of these genes and their products, based on the existing literature for each of the gene discussed. The genes we focus on are found mutated in different cognitive disorders affecting modern populations and their products are involved in skull and brain morphology, and neural connectivity. If our hypothesis turns out to be on the right track, it means that the changes affecting most of these proteins resulted in a more globular brain and ultimately brought about modern cognition, with its characteristic generativity and capacity to form and exploit cross-modular concepts, properties most clearly manifested in language.
    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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    ABSTRACT: Recent neuroimaging studies have demonstrated that Contactin-associated protein-like2 (CNTNAP2) polymorphisms affect left-hemispheric function of language processing in healthy individuals, but no study has investigated the influence of these polymorphisms on right-hemispheric function involved in human voice perception. Further, although recent reports suggest that determination of handedness is influenced by genetic effect, the interaction effect between handedness and CNTNAP2 polymorphisms for brain activity in human voice perception and language processing has not been revealed. We aimed to investigate the interaction effect of handedness and CNTNAP2 polymorphisms in respect to brain function for human voice perception and language processing in healthy individuals. Brain function of 108 healthy volunteers (74 right-handed and 34 non-right-handed) was examined while they were passively listening to reverse sentences (rSEN), identifiable non-vocal sounds (SND), and sentences (SEN). Full factorial design analysis was calculated by using three factors: (1) rs7794745 (A/A or A/T), (2) rs2710102 [G/G or A carrier (A/G and A/A)], and (3) voice-specific response (rSEN or SND). The main effect of rs7794745 (A/A or A/T) was significantly revealed at the right middle frontal gyrus (MFG) and bilateral superior temporal gyrus (STG). This result suggests that rs7794745 genotype affects voice-specific brain function. Furthermore, interaction effect was significantly observed among MFG-STG activations by human voice perception, rs7794745 (A/A or A/T), and handedness. These results suggest that CNTNAP2 polymorphisms could be one of the important factors in the neural development related to vocal communication and language processing in both right-handed and non-right-handed healthy individuals.
    Frontiers in Behavioral Neuroscience 05/2015; 9(87). DOI:10.3389/fnbeh.2015.00087 · 4.16 Impact Factor
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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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