1. ¹Laboratory of Molecular Psychiatry and Neurogenetics, University 'Campus Bio-Medico', Rome, Italy
2. ²Departments of Psychiatry and Physiology, Queens University, Kingston, ON, Canada
3. ³Medical Genetics Service, IRCCS 'Casa Sollievo dalla Sofferenza', S Giovanni Rotondo, FG, Italy
4. ⁴Department of Child Neuropsychiatry, II University of Naples, Naples, Italy
5. ⁵Neurology Service, IRCCS 'Oasi Maria SS', Troina, EN, Italy
6. ⁶Center for Autism Research and Education, Phoenix, AZ, USA
7. ⁷Southwest Autism Research and Resource Center, Phoenix, AZ, USA
8. ⁸'Associazione Anni Verdi' ONLUS, Rome, Italy
9. ⁹Department of Psychology, University 'La Sapienza', Rome, Italy
10. ¹⁰Department of Pediatric Research, Rikshospitalet, University of Oslo, Oslo, Norway
11. ¹¹Section of Neurogenetics, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
12. ¹²IRCCS 'Fondazione Santa Lucia', Rome, Italy
13. ¹³Department of Biology and Genetics, University of Milan, Milan, Italy
14. ¹⁴Department of Biostatistics and Genetic Epidemiology, Serono Genetics Institute, Evry, France
15. ¹⁵Autism Research Program, Ongwanada, Kingston, ON, Canada

Correspondence: Dr AM Persico, Laboratory of Molecular Psychiatry & Neurogenetics, University 'Campus Bio-Medico', Via Longoni 83, I-00155 Rome, Italy. E-mail: a.persico@unicampus.it

¹⁶Present address: Laboratory of Molecular Neuroembryology, IRCCS 'Fondazione Santa Lucia', Via del Fosso di Fiorano 65, I-00143, Rome, Italy.

Received 2 February 2005; Revised 17 May 2005; Accepted 3 June 2005; Published online 19 July 2005.

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: ²=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT ²=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.