Article

QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders

Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Molecular Psychiatry (Impact Factor: 14.5). 11/2011; 18(2). DOI: 10.1038/mp.2011.155
Source: PubMed

ABSTRACT

Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex. It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity. With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL). Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (P<0.0004). It was investigated using a targeted-association analysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P=0.001, 0.001, 0.002), and one was intronic to KCND3 (P=0.001). Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3. Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P=0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD. NGF is a promising risk gene for NVC deficits.Molecular Psychiatry advance online publication, 22 November 2011; doi:10.1038/mp.2011.155.

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    • "The serum NGF concentrations have been reported to be significantly higher in autistic children[54]. Another analysis suggests that NGF is a potential risk gene for nonverbal communication (NVC) impairments[55]. Recent studies have implied an association between mitochondrial dysfunction and ASD[56]. "
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    Full-text · Article · Jun 2015 · PLoS ONE
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    • "As for a potential role for NGF signaling in neuropsychiatric disorders, a quantitative trait locus (QTL) in an NGF intron was recently found to be associated with nonverbal communication in ASD subjects [102]. Also, NGF levels are reduced in an animal model of Rett Syndrome and in the serum of medication-naïve patients with SZ [103], [104]. "
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    Full-text · Article · Apr 2014 · PLoS ONE
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    • "Our novel pathway analysis supports previously published data on alterations in pathways in ASD, such as oxidative stress [61], mTOR [38], Natural Killer cells [59,60], NGF, and monocyte pathways [112], as well as activation of microglia (macrophages in the periphery) [22,109]. However, this is the first study to suggest DAS/DEU occurs in these pathways and thus confirmation is needed in a future independent cohort. "
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