A DRD1 haplotype is associated with risk for autism spectrum disorders in male-only affected sib-pair families

Authors

  • Joe A. Hettinger,

    1. Department of Physiology, Queen's University, Kingston, Ontario, Canada
    2. Autism Research Program, Ongwanada Resource Centre, Kingston, Ontario, Canada
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  • Xudong Liu,

    1. Autism Research Program, Ongwanada Resource Centre, Kingston, Ontario, Canada
    2. Department of Psychiatry, Queen's University, Kingston, Ontario, Canada
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  • Charles E. Schwartz,

    1. Center for Molecular Studies, Greenwood Genetic Center, Greenwood, South Carolina
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  • Ron C. Michaelis,

    1. Department of Biology, Western Carolina University, Cullowhee, North Carolina
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  • Jeanette J.A. Holden

    Corresponding author
    1. Department of Physiology, Queen's University, Kingston, Ontario, Canada
    2. Autism Research Program, Ongwanada Resource Centre, Kingston, Ontario, Canada
    3. Department of Psychiatry, Queen's University, Kingston, Ontario, Canada
    4. Autism Spectrum Disorders Canadian-American Research Consortium, Kingston, Ontario, Canada
    5. Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
    • Autism Research Program, Ongwanada Resource Centre, 191 Portsmouth Ave., Kingston, ON, Canada K7M 8A6.
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  • Please cite this article as follows: Hettinger JA, Liu X, Schwartz CE, Michaelis RC, Holden JJA. 2007. A DRD1 Haplotype Is Associated With Risk for Autism Spectrum Disorders in Male-Only Affected Sib-Pair Families. Am J Med Genet Part B 147B:628–636.

Abstract

Individuals with autism spectrum disorders (ASDs) have impairments in executive function and social cognition, with males generally being more severely affected in these areas than females. Because the dopamine D1 receptor (encoded by DRD1) is integral to the neural circuitry mediating these processes, we examined the DRD1 gene for its role in susceptibility to ASDs by performing single marker and haplotype case–control comparisons, family-based association tests, and genotype–phenotype assessments (quantitative transmission disequilibrium tests: QTDT) using three DRD1 polymorphisms, rs265981C/T, rs4532A/G, and rs686T/C. Our previous findings suggested that the dopaminergic system may be more integrally involved in families with affected males only than in other families. We therefore restricted our study to families with two or more affected males (N = 112). There was over-transmission of rs265981-C and rs4532-A in these families (P = 0.040, P = 0.038), with haplotype TDT analysis showing over-transmission of the C-A-T haplotype (P = 0.022) from mothers to affected sons (P = 0.013). In addition, haplotype case–control comparisons revealed an increase of this putative risk haplotype in affected individuals relative to a comparison group (P = 0.004). QTDT analyses showed associations of the rs265981-C, rs4532-A, rs686-T alleles, and the C-A-T haplotype with more severe problems in social interaction, greater difficulties with nonverbal communication and increased stereotypies compared to individuals with other haplotypes. Preferential haplotype transmission of markers at the DRD1 locus and an increased frequency of a specific haplotype support the DRD1 gene as a risk gene for core symptoms of ASD in families having only affected males. © 2008 Wiley-Liss, Inc.

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