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Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene–environment interactions

Molecular Psychiatry volume 10, pages 1006–1016 (2005)Cite this article

Abstract

Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene–environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C−108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case–control contrasts (Q192R: χ2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT χ2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.

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Acknowledgements

This work was supported by Telethon-Italy (GGP02019), the Fondation Jerome Lejeune (Paris, France), the Cure Autism Now Foundation (Los Angeles, California), and by grants from the Canadian Institutes for Health Research (#43820) and the Ontario Mental Health Foundation to JJAH. Jeanette JA Holden and Xudong Liu are members of the Autism Spectrum Disorders-Canadian-American Research Consortium (ASD-CARC; www.autismresearch.ca). We gratefully acknowledge all the families who participated in this study, Cristina Aprea for helpful comments, Joseph Piven and Thomas H Wassink for contributing DNA samples collected at the University of Iowa School of Medicine, and the resources provided by the AGRE consortium, including Daniel H Geschwind (University of California, Los Angeles), Maya Bucan (University of Pennsylvania, Philadelphia), Ted Brown (NYS Institute for Basic Research in Developmental Disabilities, New York), Joseph Buxbaum (Mt Sinai School of Medicine, New York), T Conrad Gilliam (Columbia Genome Center, New York), David A Greenberg (Mt Sinai Medical Center, New York), David H Ledbetter (Emory University, Atlanta), Stanley F Nelson (UCLA School of Medicine, Los Angeles), Jonathan Pevsner (Kennedy Krieger Institute, Baltimore), Gerard D Schellenberg (University of Washington and Veterans Affairs Medical Center, Seattle), Carol Samango-Sprouse (Children's National Medical Center, Baltimore), and Rudolph E Tanzi (Massachusetts General Hospital, Boston).

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  1. M D'Amelio

    Present address: Laboratory of Molecular Neuroembryology, IRCCS ‘Fondazione Santa Lucia’, Via del Fosso di Fiorano 65, I-00143, Rome, Italy

Authors and Affiliations

  1. Laboratory of Molecular Psychiatry and Neurogenetics, University ‘Campus Bio-Medico’, Rome, Italy

    M D'Amelio, I Ricci, R Sacco & A M Persico

  2. Departments of Psychiatry and Physiology, Queens University, Kingston, ON, Canada

    X Liu & J J A Holden

  3. Medical Genetics Service, IRCCS ‘Casa Sollievo dalla Sofferenza’, S Giovanni Rotondo, FG, Italy

    L D'Agruma, L A Muscarella & V Guarnieri

  4. Department of Child Neuropsychiatry, II University of Naples, Naples, Italy

    R Militerni & C Bravaccio

  5. Neurology Service, IRCCS ‘Oasi Maria SS’, Troina, EN, Italy

    M Elia

  6. Center for Autism Research and Education, Phoenix, AZ, USA

    C Schneider

  7. Southwest Autism Research and Resource Center, Phoenix, AZ, USA

    R Melmed

  8. ‘Associazione Anni Verdi’ ONLUS, Rome, Italy

    S Trillo

  9. Department of Psychology, University ‘La Sapienza’, Rome, Italy

    T Pascucci & S Puglisi-Allegra

  10. Department of Pediatric Research, Rikshospitalet, University of Oslo, Oslo, Norway

    K-L Reichelt

  11. Section of Neurogenetics, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

    F Macciardi

  12. IRCCS ‘Fondazione Santa Lucia’, Rome, Italy

    R Sacco, T Pascucci, S Puglisi-Allegra & A M Persico

  13. Department of Biology and Genetics, University of Milan, Milan, Italy

    F Macciardi

  14. Department of Biostatistics and Genetic Epidemiology, Serono Genetics Institute, Evry, France

    F Macciardi

  15. Autism Research Program, Ongwanada, Kingston, ON, Canada

    J J A Holden

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  1. M D'Amelio
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D'Amelio, M., Ricci, I., Sacco, R. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene–environment interactions. Mol Psychiatry 10, 1006–1016 (2005). https://doi.org/10.1038/sj.mp.4001714

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