Fabio Macciardi, Roberto Militerni, Carmela Bravaccio, Xudong Liu, Leonardo D'Agruma, Karl L. Reichelt, Roberto Sacco, I. Ricci, Simona Trillo, Cindy Schneider, Jeanette J. A. Holden, Tiziana Pascucci, Maurizio Elia, Raun Melmed, Marcello D'Amelio, Lucia Anna Muscarella, Vito Guarnieri, Antonio M. Persico, Stefano Puglisi-Allegra, D'Amelio, M, Ricci, I, Sacco, R, Liu, X, D'Agruma, L, Muscarella, La, Guarnieri, V, Militerni, R, Bravaccio, C, Elia, M, Schneider, C, Melmed, R, Trillo, S, Pascucci, T, Puglisi-Allegra, S, Reichelt, Kl, Macciardi, F, Holden, Jj, and Persico, Am.
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