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. 2013 Feb;18(2):226-35.
doi: 10.1038/mp.2011.155. Epub 2011 Nov 22.

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

A T-H Lu  1 , J Yoon, D H Geschwind, R M Cantor
Affiliations

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

A T-H Lu et al. Mol Psychiatry. 2013 Feb.

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.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Nonverbal communication (NVC) quantitative trait locus (QTL) analysis in original and replication samples.
Figure 2
Figure 2
Replicated nonverbal communcation (NVC) quantitative trait locus (QTL) on chromosome 1.
Figure 3
Figure 3
Nonverbal communcation (NVC) chromosome-1-targeted block association analysis in Autism Genetics Research Exchange (AGRE) sample.
Figure 4
Figure 4
Linkage disequilibrium and block structure for nerve growth factor (NGF) gene.
See this image and copyright information in PMC

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