title: Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions.
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: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT chi2=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.
authors: Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.
authors: M
authors: M
authors: D'Amelio
authors: I
authors: I
authors: Ricci
authors: R
authors: R
authors: Sacco
authors: X
authors: X
authors: Liu
authors: L
authors: L
authors: D'Agruma
authors: L A
authors: LA
authors: Muscarella
authors: V
authors: V
authors: Guarnieri
authors: R
authors: R
authors: Militerni
authors: C
authors: C
authors: Bravaccio
authors: M
authors: M
authors: Elia
authors: C
authors: C
authors: Schneider
authors: R
authors: R
authors: Melmed
authors: S
authors: S
authors: Trillo
authors: T
authors: T
authors: Pascucci
authors: S
authors: S
authors: Puglisi-Allegra
authors: K-L
authors: KL
authors: Reichelt
authors: F
authors: F
authors: Macciardi
authors: J J A
authors: JJ
authors: Holden
authors: A M
authors: AM
authors: Persico
mesh_terms: D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism; D001321:Autistic Disorder / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004777:Environment; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007306:Insecticides / Q000378:metabolism; D007558:Italy; D015810:Linkage Disequilibrium; D008297:Male; D008954:Models, Biological; D010755:Organophosphates / Q000378:metabolism; D010455:Peptides / Q000652:urine; D020641:Polymorphism, Single Nucleotide; D000091042:Reelin Protein; D012701:Serotonin / Q000097:blood; D014481:United States
chemical_list: D007306:Insecticides; D010755:Organophosphates; D010455:Peptides; D000091042:Reelin Protein; D012701:Serotonin; D004247:DNA; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C000717127:RELN protein, human