Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism

Conciatori, Monica; Stodgell, Christopher J.; Hyman, Susan; O’Bara, Melanie A.; Militerni, Roberto; Bravaccio, Carmela; Trillo, Simona; Montecchi, Francesco; Schneider, Cindy; Melmed, Raun D.; Elia, Maurizio; Crawford, Lori; Spence, Sarah; Muscarella, Lucia Anna; Guarnieri, Vito; D’Agruma, Leonardo; Quattrone, Alessandro; Zelante, Leopoldo; Rabinowitz, Daniel; Pascucci, Tiziana; Puglisi-Allegra, Stefano; Reichelt, Karl L.; Rodier, Patricia M.; Persico, Antonio M.

doi:10.1016/j.biopsych.2003.10.005

Cited by 96 publications

(100 citation statements)

References 47 publications

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“…Mice with disruptions of Hoxa1 have profound alterations in hindbrain organization, [255][256][257][258] which may reflect brainstem abnormalities observed in autism. 259,260 Evidence from family studies in human populations has suggested that HOXA1 is associated with genetic susceptibility for autism, 261,262 although results have been inconsistent. 263,264 A HOXA1-related disorder, Bosley-Salih -Alorainy syndrome, has been identified in a small patient sample, with symptoms that include delayed maturation and autism.…”

Section: Mouse Models Of Environmental Contributions To Autism Etiologymentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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Section: Mouse Models Of Environmental Contributions To Autism Etiologymentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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“…Demographic and clinical characteristics, as well as inclusion criteria, and diagnostic screening methods have been previously reported in detail. 31 All parents gave written informed consent for themselves and for their children, using the consent form approved by the IRB of UCBM (Rome, Italy).…”

Section: Subjectsmentioning

confidence: 99%

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

et al. 2005

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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 CÀ108T, 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: v 2 ¼ 6.33, 1 df, Po0.025), transmission/disequilibrium tests (Q192R: TDT v 2 ¼ 5.26, 1 df, Po0.025), familybased association tests (Q192R and L55M: FBAT Z ¼ 2.291 and 2.435 respectively, Po0.025), and haplotype-based association tests (L55/R192: HBAT Z ¼ 2.430, Po0.025). 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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“…[197][198][199][200][201][202][203] HOXA1 has been shown to play a role in hindbrain development in the mouse model. 204 The first positive finding 196 was not replicated despite similar or better power in most studies.…”

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confidence: 99%

“…204 The first positive finding 196 was not replicated despite similar or better power in most studies. The only additional study showing an association did find A as the risk allele, 198 whereas the first study discussed the G allele and the AG/GG genotypes as risk factors. In the former study, 198 an increased head circumference was associated with AG/GG, which might be of relevance, as a subgroup of individuals with AD does show macrocephaly.…”

mentioning

confidence: 99%

“…The only additional study showing an association did find A as the risk allele, 198 whereas the first study discussed the G allele and the AG/GG genotypes as risk factors. In the former study, 198 an increased head circumference was associated with AG/GG, which might be of relevance, as a subgroup of individuals with AD does show macrocephaly. 205,206 However, the hypothesized disrupted development of brainstem nuclei in autism 207 has not been proven by brain imaging studies.…”

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confidence: 99%

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The genetics of autistic disorders and its clinical relevance: a review of the literature

2006

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Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.

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Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism

Cited by 96 publications

References 47 publications

Advances in behavioral genetics: mouse models of autism

Advances in behavioral genetics: mouse models of autism

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

The genetics of autistic disorders and its clinical relevance: a review of the literature

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