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Cited by 807Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersChild Nutrition and Feeding Issues

Autism risk factors: genes, environment, and gene-environment interactions

Open access
Chaste, Pauline, Leboyer, Marion·2012·Dialogues in Clinical Neuroscience
DOI 10.31887/dcns.2012.14.3/pchastePMC PMC3513682
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Abstract

The aim of this review is to summarize the key findings from genetic and epidemiological research, which show that autism is a complex disorder resulting from the combination of genetic and environmental factors. Remarkable advances in the knowledge of genetic causes of autism have resulted from the great efforts made in the field of genetics. The identification of specific alleles contributing to the autism spectrum has supplied important pieces for the autism puzzle. However, many questions remain unanswered, and new questions are raised by recent results. Moreover, given the amount of evidence supporting a significant contribution of environmental factors to autism risk, it is now clear that the search for environmental factors should be reinforced. One aspect of this search that has been neglected so far is the study of interactions between genes and environmental factors.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that autism is a complex disorder resulting from combined genetic and environmental factors, with substantial genetic heterogeneity and emerging evidence for gene-environment interaction. It summarizes genetic findings (rare CNVs, synaptic pathways, exome mutations) and environmental/epidemiological risk factors, while noting that GxE research in autism remains limited.

Key findings

  • Autism is highly heritable but not Mendelian: sibling recurrence risk is 2% to 8%, rising to 12% to 20% when broader impairments are included; general-population autistic traits show heritability of 40% to 80%, and one large twin study estimated autism heritability at 55%, with a very large confidence interval of the odds ratio (9% to 81%).
  • Genetic studies implicate many rare and de novo variants, especially synaptic genes/pathways (NLGN3/NLGN4X, SHANK3, NLGN-NRXN-SHANK, SynGAP, DLGAP2) and recurrent CNVs such as 16p11; exome studies report a twofold to fourfold increase in de novo nonsense variants, and one estimate of more than 234 distinct genomic regions may be an underestimation.
  • Environmental, immune, and epigenetic evidence includes US CDC prevalence estimates rising from 1 in 110 in 2006 to 1 in 88 in 2008; prenatal valproate exposure is associated with an 8-fold increased risk of ASD; maternal gestational diabetes, bleeding, medication, and intrauterine infection are identified as risk factors; and transcriptome analysis found 444 differentially expressed genes between autistic and control cerebral cortices.
  • GxE evidence comes mainly from animal models (e.g., TSC2 haploinsufficiency plus maternal immune activation; mutant DISC1 plus immune activation), while family and population-based association studies in autism have not yet been extended to GxE.

Methods

  • Narrative review summarizing genetic and epidemiological research on autism risk factors; no new primary data or systematic meta-analysis is reported.
  • Synthesizes twin/family studies, linkage and GWAS, CNV and whole-exome studies, epigenetic/transcriptomic findings, environmental meta-analyses, and animal models of GxE.

Limitations

  • The paper states that many questions remain, including genotype-phenotype correlations, sex ratio, and intellectual disability overlap; GxE association studies in autism have not yet been extended, and power to detect GxE is lower than for main effects.
  • It notes nonreplication of many psychiatric GxE results, difficulty studying rare variant carriers, and methodological problems in perinatal studies (e.g., lack of multivariate control, co-occurring events, complications possibly secondary to familial factors).
  • Evident from the text: as a narrative review, it does not report a systematic search strategy or formal quality assessment; prevalence studies are described as not comparable in method or populations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.31887/dcns.2012.14.3/pchaste

Cites

119 of 119 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 144 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    CNVs in the NLGN-NRXN-SHANK pathway and other synaptic genes such as SynGAP and DLGAP2 are found in autism.

    “Several subsequent studies showed CNV in the NLGN-NRXN-SHANK pathway, and other synaptic genes such as SynGAP and DLGAP215,32,33”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Marshall CR., 2008, Am J Hum Genet. source

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    • cites [32] Berkel S., 2010, Nat Genet. source

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    • cites [33] Pinto D., 2010, Nature. source

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  • Interpretationreasoning

    Autism is a complex disorder resulting from the combination of genetic and environmental factors.

    “autism is a complex disorder resulting from the combination of genetic and environmental factors”
    Quote in the paperSubstantial claim
  • Premisecitation

    The three large genome-wide association studies published thus far each highlight a single, non-overlapping risk locus.

    “the three large studies using genome -wide association that have been published thus far each highlight a single, non-overlapping risk locus”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Wang K., 2009, Nature. source

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    • cites [24] Weiss LA., 2009, Nature. source

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    • cites [25] Anney R., 2010, Hum Mol Genet. source

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  • Premisecitation

    Monozygotic twins have higher concordance rates than dizygotic twins for ASDs, attention deficit hyperactivity disorder, developmental coordination disorder, and tic disorder.

    “One study showed that monozygotic twins had higher concordance rates than dizygotic twins for ASDs, attention deficit hyperactivity disorder (ADHD), developmental coordination disorder, and tic disorder”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Lichtenstein P., 2010, Am J Psychiatry. source

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  • Premisecitation

    Two of the exome sequencing studies report that spontaneous changes are correlated with paternal age.

    “two of these studies report that spontaneous changes are correlated with paternal age”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [36] Neale BM., 2012, Nature. source

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    • cites [37] O'Roak BJ., 2012, Nat Genet. source

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    • cites [38] Sanders SJ., Nature. In press.

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  • Classified as probably not a substantial claim. 19
  • The quote only partly states this claim. 2

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    Premisecitation

    Analysis of genes affected by rare CNVs confirmed the crucial role of abnormalities in synapse formation and maintenance and identified other affected pathways including cellular proliferation and motility, GTPase/Ras signaling, and neurogenesis.

    “The analysis of genes affected by rare CNVs has confirmed the crucial role of abnormalities in synapse formation and maintenance, but also identified other affected pathways, including cellular proliferation and motility, GTPase/Ras signaling, and neurogenesis”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [33] Pinto D., 2010, Nature. source

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    • cites [34] Gilman SR., 2011, Neuron. source

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    • cites [35] Ben-David E., 2012, PLoS Genet. source

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  • May combine two claims.

    Interpretationreasoning

    There is huge genetic heterogeneity in ASD, involving both locus heterogeneity and allelic heterogeneity.

    “It is now clear that there is a huge genetic heterogeneity in ASD, involving both a locus heterogeneity and an allelic heterogeneity”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent twin study estimated the heritability of autism to be 55%.

    “Another study recently challenged the high heritability model of autism, estimating the heritability of autism to be 55 %”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Hallmayer J., 2011, Arch Gen Psychiatry. source

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    Premisecitation

    Variation of autistic traits in the general population is highly heritable, at a similar level of genetic influence to autism itself, with heritability estimates of 40% to 80%.

    “the variation of autistic traits in the general population has been shown to be highly heritable, at a similar level of genetic influence to autism itself, even though the results are heterogeneous (heritability 40% to 80%)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Constantino JN., 2003, Arch Gen Psychiatry. source

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    • cites [10] Ronald A., 2006, J Am Acad Child Adolesc Psychiatry. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent studies have estimated the prevalence of pervasive developmental disorders to be as high as one child in 38.

    “recent studies have gone so far as to estimate the prevalence to be one child in 38”
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    • cites [59] Kim YS., 2011, Am J Psychiatry. source

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    Premisecitation

    Another study suggested that diagnostic substitution and better ascertainment explain only a part of the linear increase observed in the California registry.

    “another study suggested that diagnostic substitution, especially for the most severe cases, and better ascertainment, especially for children at the less severe end of the spectrum, explain only a part of the linear increase observed in the California registry”
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    • cites [62] King M., 2009, Int J Epidemiol. source

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    Premisecitation

    An English epidemiological study based on a national sample from 2007 found a rate of about 1% in adults across the entire age range, without a significant reduction in the older part of the sample.

    “the authors found a rate of about 1% in adults across the entire age range, without a significant reduction in the older part of the sample”
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    • cites [61] Brugha TS., 2011, Arch Gen Psychiatry. source

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    Premisecitation

    A recent large-scale CNV study showed a strong effect of large rare gene de novo CNVs on the presence or absence of an ASD diagnosis, but did not support IQ as a useful predictor for probands carrying these risk variants.

    “a recent large-scale CNV study showing a strong effect of large rare genie de novo CNVs on the presence or absence of an ASD diagnosis, but did not support IQ as a useful predictor for probands carrying these risk variants”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Sanders SJ., 2011, Neuron. source

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    Premisecitation

    Intellectual disability is present in 65% to 75% of individuals with a strict diagnosis of autistic disorder, and in 30% to 55% if all ASDs are considered.

    “Intellectual disability (ID) is present in 65% to 75% ol individuals with a strict diagnosis of autistic disorder, and in 30% to 55% if all ASDs are considered”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Baird G., 2006, Lancet. source

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    • cites [55] Chakrabarti S., 2005, Am J Psychiatry. source

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    Premisecitation

    Two discrete modules of coexpressed genes associated with autism were identified; the first module, related to synaptic function and neuronal projection, was underexpressed in autism cases, and the second, enriched for immune genes and glial markers, was overexpressed.

    “the authors identified two discrete modules of coexpressed genes associated with autism. While the first module, which is related to synaptic function and neuronal projection, was underexpressed in autism cases, the second module, which was enriched for immune genes and glial markers, was overexpressed”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Voineagu I., 2011, Nature. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The CDC prevalence estimate reached 1 in 88 children in 2008, while the previous estimate was one in 110 in 2006.

    “The last prevalence estimates in the United States, released by the Centers for Disease Control recently,60 reached 1 in 88 child in 2008, while their previous estimate was one in 110 in 2006”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Investigators. AaDDMNSYP. Prevalence of autism spectrum disorders autism and developmental disabilities monitoring network, 14 sites. United States, 2008., 2012, MMWR Surveill Summ.

      Not checked in the free run.

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    Premisecitation

    Studies have shown abnormalities in the peripheral immune system in autism such as T-cell dysfunction, autoantibody production, increase in the number of activated B cells and NK cells, and increase in proinflammatory cytokines.

    “several studies have shown abnormalities in the peripheral immune system such as T-cell dysfunction, autoantibody production, increase in the number of activated B cells and NK cells, and increase in proinflammatory cytokines”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [64] Gupta S., 1998, J Neuroimmunol. source

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    • cites [65] Singh VK., 1997, Pediatr Neurol. source

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    • cites [66] Ashwood P., 2011, PLoS One. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent analysis suggests that common and rare variants contribute to ASD by perturbation of common neuronal networks.

    “a recent analysis of genetic variations associated with ASD suggests that common and rare variants contribute to ASD by perturbation of common neuronal networks”
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    • cites [35] Ben-David E., 2012, PLoS Genet. source

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    Premisecitation

    Rett syndrome is caused by a mutation of methyl-CpG-binding protein 2 (MeCP2), which binds to methylated DNA and represses the transcription of target genes.

    “there are abnormalities of transcriptional regulation in Rett syndrome, caused by a mutation of methyl-CpGbinding protein 2 (MeCP2). Indeed, MeCP2 binds to methylated DNA and represses the transcription of target genes”
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    • cites [70] Chahrour M., 2008, Science. source

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    Premisecitation

    The prevalence of pervasive developmental disorders was estimated at 6 per 1000 in a population of school children in 2005.

    “the prevalence was estimated at 6 per 1000 in a population of school children in 2005”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Fombonne E., 2005, J Clin Psychiatry.

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    Premisecitation

    The authors did not find evidence for a genetic etiology for the upregulation of the genes of the second module, suggesting that it is probably a nongenetic, adaptive, or environmental process.

    “the authors did not find any evidence for a genetic etiology for the upregulation of the genes of the second module, suggesting that it is probably a nongenetic, adaptive, or environmental process”
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    • cites [69] Voineagu I., 2011, Nature. source

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    Premisecitation

    SHANK3 and NRXN1 genes were suggested to be involved in schizophrenia.

    “STIANK3 and NRXN1 genes were also suggested to be involved in schizophrenia”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [44] Gauthier J., 2010, Proc Natl Acad Sci U S A. source

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    • cites [45] Vrijenhoek T., 2008, Am J Hum Genet. source

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    • cites [46] Need AC., 2009, PLoS Genet. source

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  • May combine two claims.

    Interpretationreasoning

    It seems reasonable to think that there may be both a real increase in the number of cases and an increase in the detection of affected children.

    “it seems reasonable to think that there may be both a real increase in the number of cases and an increase in the detection of affected children”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Feeding difficulties and congenital malformation should rather be considered as symptoms of an underlying cause of autism.

    “Feeding difficulties and congenital malformation that are also mentioned should rather be considered as symptoms of an underlying cause of autism”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Most of these subjects were born preterm (96.7%); 32.3% were small for gestational age; the authors did not use multivariate analyses to simultaneously control for birth weight and gestational age.

    “Most of these subjects were born preterm (96.7%); however, 32.3% were small for gestational age and the authors did not use multivariate analyses to simultaneously control for birth weight and gestational age”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Pinto-Martin JA., 2011, Pediatrics. source

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    Premisecitation

    A recent study based on rigorous diagnostic assessment using validated instruments suggested an association between preterm birth and risk for ASD.

    “a recent study based on rigorous diagnostic assessment using validated instruments suggested an association between preterm birth and risk for ASD”
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    • cites [85] Pinto-Martin JA., 2011, Pediatrics. source

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  • May combine two claims.

    Interpretationreasoning

    The methodological issue of not controlling for simultaneous events concerns most studies on perinatal and neonatal risk factors, making it difficult to interpret their results.

    “This methodological issue concerns most of the studies on perinatal and neonatal risk factors, which makes it difficult to interpret the results of these studies, since many of the events studied are likely to occur at the same time”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Children of migrant parents are at an increased risk of autism with intellectual disability, especially when parents migrated to Sweden from regions with a low human development index, and a decreased risk of high-functioning autism.

    “children of migrant parents are at an increased risk of autism with intellectual disability, especially when parents migrated to Sweden from regions with a low human development index, and a decreased risk of high-functioning autism”
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    • cites [89] Magnusson C., 2012, Br J Psychiatry. source

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    Premisecitation

    Selective serotonin reuptake inhibitor medication use during pregnancy increased from 1.5% in 1996 to 6.4% in 2004 and 6.2% in 2005.

    “selective serotonin reuptake inhibitor medication during pregnancy increased from 1.5% in 1996 to 6.4% in 2004 and 6.2% in 2005.92”
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    • cites [92] Andrade SE., 2008, Am J Obstet Gynecol. source

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    Interpretationcitation

    Gestational viral infections trigger a maternal immune response, which can perturb fetal brain development, at least in part through interleukin-6.

    “It seems that gestational viral infections trigger a maternal immune response, which can perturb fetal brain development, at least in part through interleukin-6”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Smith SE., 2007, J Neurosci. source

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    Interpretationcitation

    Individuals with autism may react differently to the same environmental stimuli and may have less tolerance to the prenatal experience compared with their siblings.

    “This suggested that individuals with autism may react differently to the same environmental stimuli and may have less tolerance to the prenatal experience compared with their siblings.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Glasson EJ., 2004, Arch Gen Psychiatry. source

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    Premisecitation

    A recent meta-analysis of prenatal factors, limited to pregnancy-related factors, identified few significant risk factors; the main factors are maternal gestational diabetes, maternal bleeding during pregnancy, and maternal medication.

    “A recent meta-analysis of prenatal factors, limited to pregnancy-related factors, identified few significant risk factors.81 The main factors are maternal gestational diabetes, maternal bleeding during pregnancy, and maternal medication”
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    • cites [81] Gardener H., 2009, Br J Psychiatry. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some studies have suggested that increased rates of birth and pregnancy complications are likely secondary to familial factors associated with autism.

    “some studies have suggested that increased rates of birth and pregnancy complications are likely secondary to familial factors associated with autism”
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    • cites [86] Zwaigenbaum L., 2002, J Am Acad Child Adolesc Psychiatry. source

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    Premisecitation

    In Turner's syndrome, women who have monosomy of the X chromosome (X0) often have autistic traits which are correlated with the parental origin of the X chromosome they received.

    “in Turner's syndrome, women who have monosomy of the X chromosome (X0), often have autistic traits which are correlated with the parental origin of the X chromosome they received”
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    • cites [73] Skuse DH., 1997, Nature. source

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    Premisecitation

    Another meta-analysis focusing on the perinatal and neonatal period identified several potential risk factors, the main being fetal presentation, umbilical-cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age, low 5-minute Apgar score, meconium aspiration, neonatal anemia, ABO or Rh incompatibilty

    “In another meta-analysis focusing on the perinatal and neonatal period,83 the same authors identified several potential risk factors, the main being fetal presentation, umbilieal-cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age, low 5minute Apgar score, meconium aspiration, neonatal anemia, AB”
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    • cites [83] Gardener H., 2011, Pediatrics. source

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    Interpretationnone given

    Genetic heterogeneity can explain the absence of replication of association studies in autism.

    “Genetic heterogeneity can be one explanation for the absence of replication of association studies in autism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In an epidemiological study on autism including a comparison group of siblings, unaffected siblings had fewer prenatal and perinatal complications than their affected siblings, but more than control subjects.

    “in an epidemiological study on autism that included a comparison group of siblings,96 unaffected siblings had fewer prenatal and perinatal complications than their affected siblings, but more than control subjects.”
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    • cites [96] Glasson EJ., 2004, Arch Gen Psychiatry. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    This study estimated the prevalence to be 5% in adolescents who had a birth weight <2000 g in the US, which is significantly greater than the last national prevalence estimates.

    “This study estimated the prevalence to be 5% in adolescents who had a birth weight <2000 g in the US, which is significantly greater than the last national prevalence estimates”
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    • cites [85] Pinto-Martin JA., 2011, Pediatrics. source

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    Premisecitation

    The Autism Birth Cohort will follow 100,000 children from conception to age 7.

    “The Autism Birth Cohort will follow 100 000 children from conception to age 7.110”
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    • cites [110] Stoltenberg C., 2010, Mol Psychiatry. source

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    Premisecitation

    The National Children's study will follow 100,000 children in the US from conception to age 21.

    “The National Children's study will follow 100 000 children in the US from conception to age 21.109”
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    • cites [109] Landrigan PJ., 2006, Pediatrics. source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Several perinatal and neonatal risk factors identified by Gardener et al. may be associated with an increased risk of hypoxia.

    “Gardener et al81 noted that several of the perinatal and neonatal risk factors they identified may be associated with an increased risk of hypoxia.”
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    • cites [81] Gardener H., 2009, Br J Psychiatry. source

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    Premisecitation

    Low plasma melatonin concentration is a frequent trait in ASD patients, caused by a primary deficit in acetylserotonin-methyl-transferase (ASMT) activity.

    “low plasma melatonin concentration is a frequent trait in ASD patients,100,101caused by a primary deficit in acetylserotonin-melhyl-transferase (ASMT) activity.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100] Melke J., 2008, Mol Psychiatry. source

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    • cites [101] Tordjman S., 2005, Biol Psychiatry. source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Recent advances in genetics have allowed a new conceptualization of molecular and cellular mechanisms of the pathology.

    “recent advances in genetics have allowed a new conceptualization of molecular and cellular mechanisms of the pathology.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from animal models of GxE interactions are informative about GxE interactions in human autism.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Major advances have been made in the past decade in understanding autism risk.

    “major advances have been made in the past decade in this domain.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from animal models of GxE interactions are informative about GxE interactions in human autism.

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Premisecitation

    In children with ADHD, the 5-HTTLPR S/S genotype interacted with low birth weight, increasing rigid behavior.

    “also interacted with low birth weight, increasing rigid behavior.111”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Nijmeijer JS., 2010, J Child Psychol Psychiatry. source

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  • The quote only partly states this claim.

    Interpretationcitation

    Late gestation is the main period of vulnerability of neurodevelopment to flu infection.

    “These results suggest that late gestation is the main period of vulnerability of neurodevelopment to flu infection”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Ehninger D., 2012, Mol Psychiatry. source

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41 of 41

  • The paper relies on this without support.

    The study of interactions between genes and environmental factors has been neglected so far.

    “One aspect of this search that has been neglected so far is the study of interactions between genes and environmental factors”

  • The paper relies on this without support.

    Autism is not Mendelian in at least a vast majority of cases.

    “The only consensus regarding the mode of inheritance of autism is that it is not Mendelian, at least in a vast majority of cases”

  • The paper relies on this without support.

    Family and population-based association studies in autism have not yet been extended to GxE interaction.

    “family and population-based association studies in autism have not been extended for GxE interaction yet.”

  • The paper relies on this without support.

    Findings from animal models of GxE interactions are informative about GxE interactions in human autism.

    “available evidence for the contribution of GxE to autism risk comes from animal models.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The fact that the concordance is less than 100% in monozygotic twins indicates that environmental and epigenetic factors are also involved in ASD.

    “However, the fact that the concordance is less than 100% in monozygotic twins indicates that environmental and epigenetic factors are also involved [96].”

    From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [96]

    The Genetic epidemiology section (page unavailable) reports higher ASD concordance in monozygotic than dizygotic twins and discusses a twin-study heritability estimate of 55%. The Epigenetic dysregulation in autism section (page unavailable) describes evidence for epigenetic involvement and a possible role for environmental factors. The paper does not explicitly give a below-100% monozygotic concordance rate or draw the claimed inference from twin discordance to both environmental and epigenetic factors. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • ASD is by now considered as a multifactorial disease.

    “For this reason, ASD is by now considered as a multifactorial disease [95,96,97].”

    From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [96]

  • Gene x environment interactions are likely to play a role in most etiologies.

    “Gene x environment interactions are likely to play a role in most etiologies 42.”

    From Gastrointestinal Issues and Autism Spectrum Disorder (2020) · cites this paper as [42]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting estimates of ASD-associated genomic regions

    Minor

    The text describes the estimate from reference 39 as "up to 234" loci, while Table I describes it as more than 234 genomic regions. Those bounds cannot both describe the same estimate.

  • The same article has conflicting publication details

    Minor

    References 16 and 37 give the same title, PMID, and PMC identifier, but assign the article different publication years, volumes, and pages.

2 of 2

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 5

  1. American Psychiatric Association., 1994, Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association;
  2. Jorde LB., 1991, Am J Hum Genet., 49, 932
  3. Pickles A., 1995, Am J Hum Genet., 57, 717
  4. Sanders SJ., Nature. In press.
  5. Fombonne E., 2005, J Clin Psychiatry., 66, 3

Cited by

Sorted by citations

Related

Authors
Chaste, P., & Leboyer, M.
Affiliations
Inserm (FR)
Corresponding author
Leboyer, Marion
ORCID
Venue
Dialogues in Clinical Neuroscience
Publisher
Informa UK Limited
Published
2012-09-30
Volume
14
Issue
3
Pages
281-292
ISSN
  • 1294-8322 (ISSN-L)
  • 1958-5969
DOI
10.31887/dcns.2012.14.3/pchaste
PMC
PMC3513682
OpenAlex
W15569989
Semantic Scholar
e7865371925d00a535ddd5610fcc62289c2d6a29
Cited by
807
References
119
Citations by year
2026: 49 · 2025: 68 · 2024: 86 · 2023: 90 · 2022: 108 · 2021: 100 · 2020: 77 · 2019: 50 · 2018: 44 · 2017: 41 · 2016: 31 · 2015: 29 · 2014: 21 · 2013: 8 · 2012: 2
FWCI
9.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Dialogues in Clinical Neuroscience (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
Keywords
autism spectrum disorder, autism risk factors, genetic factors, environmental factors, gene-environment interaction, genetic susceptibility, autism genetics
MeSH terms
Autistic Disorder, Environment, Humans, Risk Factors, Molecular Epidemiology, Gene Dosage, Genetic Predisposition to Disease, Gene-Environment Interaction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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