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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
Open accessAbstract
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.
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“At the same time, autism is associated with RELN gene variants yielding reduced Reelin gene expression both in vitro and in vivo, and with PON1 gene variants responsible for lower gene expression and reduced detoxification of some OP compounds [140, 239, 240].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [239]
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Metadata
- Authors
- D'Amelio, M., Ricci, I., Sacco, R., Liu, X., D'Agruma, L., Muscarella, L. A., Guarnieri, V, Militerni, R., Bravaccio, C., Elia, M., Schneider, C., Melmed, R., Trillo, S., Pascucci, T., Puglisi-Allegra, S., Reichelt, K.-L., Macciardi, F., Holden, J. J. A., & Persico, A. M.
- Affiliations
- Università Campus Bio-Medico (IT)
- Queen's University (CA)
- Casa Sollievo della Sofferenza (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Oasi Maria SS (IT)
- Southwest Autism Research & Resource Center (US)
- Ministry of Defence (IT)
- Fondazione Santa Lucia (IT)
- University of Oslo (NO)
- Centre for Addiction and Mental Health (CA)
- Corresponding author
- Persico, A M
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2005-07-19
- Volume
- 10
- Issue
- 11
- Pages
- 1006-1016
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2068923820
- Cited by
- 125
- References
- 68
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 1 · 2018: 6 · 2017: 7 · 2016: 5 · 2015: 8 · 2014: 8 · 2013: 2 · 2012: 10
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pesticide Exposure and Toxicity
- Keywords
- autism spectrum disorder, paraoxonase 1, organophosphate exposure, gene-environment interaction, autism pathogenesis, diazinon, pesticide exposure, neuronal migration, transmission disequilibrium test, family-based association, haplotype association, single nucleotide polymorphisms
- MeSH terms
- Reelin Protein, Autistic Disorder, Base Sequence, Child, DNA, DNA Mutational Analysis, Environment, Female, Humans, Insecticides, Italy, Male, Models, Biological, Peptides, Organophosphates, Serotonin, United States, Genetic Variation, Linkage Disequilibrium, Case-Control Studies, Polymorphism, Single Nucleotide, Aryldialkylphosphatase
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