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

Molecular Psychiatry volume 18, pages 226–235 (2013)Cite this article

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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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Acknowledgements

These analyses were supported by NIH/NIMH Autism Center of Excellence network Grant MH081754 to Daniel Geschwind (PI). We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by Grant 1U24MH081810 from the National Institute of Mental Health to Clara M Lajonchere (PI). The AGRE Consortium: Dan Geschwind, MD, PhD, UCLA, Los Angeles, CA; Maja Bucan, PhD, University of Pennsylvania, Philadelphia, PA; W Ted Brown, MD, PhD, FACMG, NYS. Institute for Basic Research in Developmental Disabilities, Staten Island, NY; Rita M Cantor, PhD, UCLA School of Medicine, Los Angeles, CA; John N Constantino, MD, Washington University School of Medicine, St Louis, MO; T Conrad Gilliam, PhD, University of Chicago, Chicago, IL; Martha Herbert, MD, PhD, Harvard Medical School, Boston, MA Clara Lajonchere, PhD, Autism Speaks, Los Angeles, CA; David H Ledbetter, PhD, Emory University, Atlanta, GA; Christa Lese-Martin, PhD, Emory University, Atlanta, GA; Janet Miller, JD, PhD, Autism Speaks, Los Angeles, CA; Stanley F Nelson, MD, UCLA School of Medicine, Los Angeles, CA; Gerard D Schellenberg, PhD, University of Washington, Seattle, WA; Carol A Samango-Sprouse, EdD, George Washington University, Washington, DC; Sarah Spence, MD, PhD, UCLA, Los Angeles, CA; Matthew State, MD, PhD, Yale University, New Haven, CT Rudolph E Tanzi, PhD, Massachusetts General Hospital, Boston, MA. CIDR Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number N01-HG-65403. The authors gratefully acknowledge the families participating in the Autism Genome Project (AGP) and the main funders: Autism Speaks (USA), the Health Research Board (HRB; Ireland), the Medical Research Council (MRC; UK), Genome Canada/Ontario Genomics Institute and the Hilibrand Foundation (USA).

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  1. A T-H Lu and J Yoon: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

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

  2. Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    D H Geschwind & R M Cantor

  3. Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    D H Geschwind

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  1. A T-H Lu
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Correspondence to R M Cantor.

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Lu, AH., Yoon, J., Geschwind, D. et al. QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders. Mol Psychiatry 18, 226–235 (2013). https://doi.org/10.1038/mp.2011.155

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