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Cited by 375Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersGenetic Associations and Epidemiology

Individual common variants exert weak effects on the risk for autism spectrum disorders

Open access
Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven +129 more·2012·Human Molecular Genetics
DOI 10.1093/hmg/dds301PMC PMC3471395
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Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

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Written from the paper’s full text.

TL;DR

Stage 2 of the Autism Genome Project GWAS added 1301 ASD families to Stage 1, yielding 2705 families and over 947,000 QC-passed SNPs, but found no genome-wide significant single-SNP association with ASD. Common variants en masse significantly predicted Stage 2 case status, yet explained <1% of variance, supporting individually weak but collectively detectable common-variant effects.

Key findings

  • No single SNP reached genome-wide significance (P < 5 × 10−8); the distribution of test statistics was consistent with chance. Four primary-analysis regions had uncorrected P < 10−6, including rs4150167 in TAF1C (Spectrum/All ancestries; overall P = 2.910e-07, OR = 0.51; Stage 1 OR = 0.37, Stage 2 OR = 0.65, P = 0.014).
  • The strongest uncorrected association across all analyses was rs1718101 in CNTNAP2 in European individuals with higher IQ (P = 7.8 × 10−9; OR = 2.13). It also showed modest association with age-at-first-phrase (additive P = 0.017; dominant P = 0.015), while rs17236239 showed recessive association with age-at-first-phrase (P = 0.018) and rs2710102 showed modest ASD risk association (P = 0.045).
  • Stage 1-derived allele scores significantly predicted Stage 2 case versus pseudo-control status, but explained little variance: always <1%, with the greatest signal in European ancestry individuals with strict autism diagnosis (Vm = 0.78%; empirical P < 0.001). Most variance accrued to the minor allele frequency quintile 0.2–0.3.
  • The previously highlighted MACROD2 SNP rs4141463 showed little Stage 2 signal (Stage 1 P = 2.40 × 10−8, OR = 0.65; Stage 2 P = 0.206, OR = 0.91; combined P = 1.2 × 10−6, OR = 0.77).

Methods

  • The Autism Genome Project Stage 2 GWAS added 1301 ASD families to Stage 1, for a combined 2705 families; genotyping used Illumina Infinium 1M-single or 1M-duo arrays, with 947,233 SNPs passing QC.
  • Primary family-based association analyses used an additive model across four overlapping datasets defined by diagnosis (spectrum vs strict) and ancestry (all ancestries vs European); secondary analyses examined parent-of-origin, verbal/non-verbal status, IQ, and age at first word/phrase using FBAT and in-house family-based methods.
  • Allele scores were built from Stage 1 GWA signals at 10 P-value thresholds (P < 0.5 to P < 0.00001), then tested in Stage 2 via logistic regression predicting case status against pseudo-controls, with ancestry and non-missing genotype counts as covariates; variance explained was estimated by Nagelkerke pseudo R-squared difference and empirical significance by 1000 permutations.

Limitations

  • The paper states that the allele-score analysis assumes pseudo-control liability distribution resembles the general population; an excess of multiplex families (at least 33% of families studied; 47.5% simplex, 19.5% unknown) could substantially bias Vm downward, and a larger Stage 1 predictor sample would improve score accuracy.
  • The paper states that power to detect a protective effect for rs4150167 is small, so the posterior probability that this observation is a false positive is large; secondary-analysis P-values are uncorrected for multiple testing and none should be considered significant.
  • Evident from the text: the top uncorrected CNTNAP2 SNP rs1718101 was not supported by other genotyped SNPs in LD, and the sample was predominantly European ancestry (94.9% of probands), limiting generalization and independent confirmation.

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

Integrity signals

Registry

Crossref · 10.1093/hmg/dds301

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Exploratory analyses produce no significant findings after adjusting for multiple testing.

    “Exploratory analyses also produce no significant findings after adjusting for multiple testing (Table 3).”
    Quote in the paperSubstantial claim
  • Findingown data

    Most of the variance explained accrues to the minor allele frequency quintile 0.2-0.3.

    “Analyses stratifying by quintile of minor allele frequency showed that most of the variance explained accrues to the quintile 0.2–0.3 (Supplementary Material, Fig. S6).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample.

    “In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample.”
    • Also stated in: § RESULTS · plain
      “When examined against Stage 2 individuals, the Stage 1 scores were significant predictors of case status (Fig. 1) and thus explain a significant portion of variance in case and control status of Stage 2 samples.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Individual common variants exert only a limited effect on risk and many such variants are present and exert these effects independently.
  • Findingown data

    The variance explained by the allele scores was small (Vm < 1%).

    “Despite being significant, the variance explained by these allele scores was small (Vm< 1%).”
    • Also stated in: § RESULTS · plain
      “Still the markers explain only a small proportion of the variance—always <1%, with the greatest signal observed in the smallest yet most homogeneous group, namely European ancestry individuals with a Strict diagnosis of autism (Vm = 0.78%; Empirical P< 0.001).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The distribution of liability for pseudo controls is similar to that of the general population.
  • Findingown data

    No single SNP shows significant association with ASD or selected phenotypes at a genome-wide level.

    “Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level.”
    • Also stated in: § RESULTS · plain
      “Association analyses of these four classes do not identify any single SNP to be significantly associated with autism as judged by an accepted threshold for genome-wide significance, P < 5 × 10−8.”
    • Also stated in: § DISCUSSION · plain
      “From this large data set, we observed no genome-wide significant association with specific common variants.”
    Quote in the paperSubstantial claim
  • May combine two claims. 11
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Findingown data

    The same pattern of over-transmission of the common allele is present in the Stage 2 sample and cannot be traced to a genotyping error.

    “The same pattern, although not as extreme, is present in the Stage 2 sample and again cannot be traced to a genotyping error (Supplementary Material, Fig. S7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The common allele for rs4150167 was over-transmitted and is represented on roughly 98% of the chromosomes.

    “Of interest is that the common allele for rs4150167 was over-transmitted and is represented on roughly 98% of the chromosomes.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The SNP that achieves the smallest P-value from secondary analyses is rs1718101.

    “The SNP that achieves the smallest P-value from secondary analyses is rs1718101.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    94.9% of the probands are of European ancestry.

    “Ancestry analysis, estimated from numerous genetic markers by using standard techniques (31–33) and mapped back onto European recruitment sites to anchor the common ancestry of subjects, showed that 94.9% of the probands are of European ancestry (Supplementary Material, Fig. S1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Only four genomic regions show association signals at P < 10−6, two falling in genes.

    “Only four genomic regions show association signals at P < 10−6, two falling in genes (Table 2; Supplementary Material, Figs S4 and 5).”
    Quote in the paperSubstantial claim

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

    Findingown data

    rs1718101 falls in CNTNAP2.

    “It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD.”
    • Also stated in: § DISCUSSION · plain
      “The SNP resides within CNTNAP2 (7q35), which encodes the Contactin-associated protein-like 2, a member of the neurexin-family thought to play a role in axonal differentiation and guidance.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The region encompassed by these three SNPs captures the 3′ region of a putative antisense RNA, specifically CR596518, and one SNP falls in its translated region (rs14135).

    “The region encompassed by these three SNPs captures the 3′ region of a putative antisense RNA, specifically CR596518, and one SNP falls in its translated region (rs14135).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    rs1718101 shows modest, significant association with age-at-first-phrase, acting either additively or dominantly but not recessively.

    “For the language outcomes, rs1718101 shows modest, significant association with age-at-first-phrase, acting either additively or dominantly but not recessively; rs17236239 shows modest association with age-at-first-phrase under a recessive model (Table 5).”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    If rs4150167 were a true causal effect, the minor allele is protective.

    “If this were a true causal effect, it suggests that the minor allele at rs4150167 is somehow protective.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    CNTNAP2 has previously been implicated in ASD, in part because it resides within regions of suggestive linkage.

    “CNTNAP2 is one of the largest genes in the human genome encompassing ∼1.5% of chromosome 7 and has previously been implicated in ASD, in part because it resides within regions of suggestive linkage (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Liu, 2001, A genomewide screen for autism susceptibility loci, Am. J. Hum. Genet. source

      Not checked in the free run.

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

    Study design and conductown data

    Examination of genotype intensity plots showed good quality clustering for rs1718101.

    “Examination of the genotype intensity plots, however, showed good quality clustering (Supplementary Material, Fig. S7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Common variants affect the risk for ASD but their individual effects are modest.

    “Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The distribution of liability for pseudo controls is similar to that of the general population.
    • The authors state this as an assumption: Individual common variants exert only a limited effect on risk and many such variants are present and exert these effects independently.

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

    Premisecitation

    Common variants in CNTNAP2 have also been associated with ASD and specific-language impairment.

    “Common variants in CNTNAP2 have also been associated with ASD (49–51) and specific-language impairment (52).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [49] Alarcon, 2008, Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene, Am. J. Hum. Genet. source

      Not checked in the free run.

    • cites [50] Arking, 2008, A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism, Am. J. Hum. Genet. source

      Not checked in the free run.

    • cites [51] Bakkaloglu, 2008, Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders, Am. J. Hum. Genet. source

      Not checked in the free run.

    • cites [52] Vernes, 2008, A functional genetic link between distinct developmental language disorders, N. Engl. J. Med. source

      Not checked in the free run.

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

    Premisecitation

    Rare variation in CNTNAP2, including CNVs, other structural disruptions and deleterious sequence variation, has been identified in subjects with autism, epilepsy, intellectual disability, Pitt-Hopkins-like syndrome, schizophrenia and Tourette syndrome.

    “More directly, rare variation in CNTNAP2, including CNVs, other structural disruptions and deleterious sequence variation, has been identified in subjects with autism, epilepsy, intellectual disability, Pitt-Hopkins-like syndrome, schizophrenia and Tourette syndrome (42–48), albeit with differing degrees of evidence for effect on these traits.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [42] Mikhail, 2011, Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders, Am. J. Med. Genet. A source

      Not checked in the free run.

    • cites [43] Gregor, 2011, Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1, BMC Med. Genet. source

      Not checked in the free run.

    • cites [44] Sehested, 2010, Deletion of 7q34-q36.2 in two siblings with mental retardation, language delay, primary amenorrhea, and dysmorphic features, Am. J. Med. Genet. A source

      Not checked in the free run.

    • cites [45] Mefford, 2010, Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies, PLoS. Genet. source

      Not checked in the free run.

    • cites [46] Zweier, 2009, CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila, Am. J. Hum. Genet. source

      Not checked in the free run.

    • cites [47] Poot, 2010, Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder, Neurogenetics source

      Not checked in the free run.

    • cites [48] Jackman, 2009, Gene associated with seizures, autism, and hepatomegaly in an Amish girl, Pediatr. Neurol. source

      Not checked in the free run.

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

    Premisecitation

    Use of a larger sample size to develop the predictor should produce a more accurate allele score and thus increase the amount of variance in Stage 2 case and control status explained.

    “In addition, as pointed out by Ripke et al. (37), the use of a larger sample size to develop the predictor (i.e. model from the Stage 1 sample) should produce a more accurate allele score and thus increase the amount of variance in the Stage 2 case and control status explained.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Ripke, 2011, Genome-wide association study identifies five new schizophrenia loci, Nat. Genet. 43 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The protective allele results in a non-synonymous glycine to arginine change at amino acid position 523 and has also been implicated in alternate splicing.

    “The protective allele results in a non-synonymous glycine to arginine change at amino acid position 523 and has also been implicated in alternate splicing (38), both of which offer a starting point for investigation of the impact of this variation on gene function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Hiller, 2006, Single-nucleotide polymorphisms in NAGNAG acceptors are highly predictive for variations of alternative splicing, Am. J. Hum. Genet. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    All quality control (QC) procedures were consistent across data sets.

    “All quality control (QC) procedures were consistent across data sets and are described elsewhere (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Anney, 2010, A genome-wide scan for common alleles affecting risk for autism, Hum. Mol. Genet. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Earlier analyses predicted that few if any common variants have an impact on risk exceeding 1.2 (or below its inverse).

    “These analyses predicted that few if any common variants have an impact on risk exceeding 1.2 (or below its inverse).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Devlin, 2011, Do common variants play a role in risk for autism? Evidence and theoretical musings, Brain Res. source

      Not checked in the free run.

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

    Premisecitation

    Antisense RNA can play a role in the mechanics of imprinting.

    “Because antisense RNA can play a role in the mechanics of imprinting (53), this observation is of some note.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Williamson, 2011, Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster, PLoS Genet. source

      Not checked in the free run.

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

    Premisecitation

    Recent studies of rare variants find it challenging to distinguish risk variation from the background stochastic noise.

    “Qualitatively, recent studies of rare variants also find it challenging to distinguish risk variation from the background stochastic noise (12–15).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [12] Sanders, 2012, Disruptive de novo point mutations, revealed by whole-exome sequencing, are strongly associated with Autism Spectrum Disorders, Nature source

      Not checked in the free run.

    • cites [13] O'Roak, 2012, Sporadic autism exomes reveal a highly interconnected network of de novo mutations, Nature source

      Not checked in the free run.

    • cites [14] Neale, 2012, Patterns and rates of exonic de novo mutations in autism spectrum disorders, Nature source

      Not checked in the free run.

    • cites [15] Iossifov, 2012, De novo gene disruptions in children on the autistic spectrum, Neuron source

      Not checked in the free run.

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

    Study design and conductown data

    No duplicate samples were found between Stages 1 and 2, or within the Stages.

    “we searched the data set for duplicate samples between Stages 1 and 2, as well as within the Stages, and found none”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    A total of 947,233 SNPs passed QC for the combined data sets.

    “A total of 947 233 SNPs passed QC for the combined data sets.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    Without additional biological or statistical evidence, the MACROD2 result is unconvincing.

    “Nonetheless, without additional biological or statistical evidence, the result is unconvincing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The analyses in Devlin et al. (28) cannot be precise when predicting the number of loci with common variants of modest impact on risk (0.8< risk <1.2); the modelling is consistent with a range of loci from zero to many thousands.

    “The analyses laid out in Devlin et al. (28) cannot be precise when predicting the number of loci with common variants of modest impact on risk (0.8< risk <1.2); the modelling is consistent with a range of loci from zero to many thousands.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Devlin, 2011, Do common variants play a role in risk for autism? Evidence and theoretical musings, Brain Res. source

      Not checked in the free run.

24 of 24

  • The authors state this as an assumption.

    The distribution of liability for pseudo controls is similar to that of the general population.

    “Importantly the allele-score analysis assumes that the distribution of liability for pseudo controls is similar to that of the general population.”

  • The authors state this as an assumption.

    Individual common variants exert only a limited effect on risk and many such variants are present and exert these effects independently.

    “Under the hypothesis that individual common variants exert only a limited effect on risk and that many such variants are present and exert these effects independently, we would expect these effects to be detectable in an analysis of common variants en masse.”

  • The authors state this as an assumption.

    The primary analyses assume an additive model for the effect of transmitted alleles on the risk of ASD.

    “the primary analyses assume an additive model”
3 of 3

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 study reports the first common risk variants robustly associated with ASD by more than doubling the discovery sample size compared to previous GWAS.

    “Here we report the first common risk variants robustly associated with ASD by more than doubling the discovery sample size compared to previous GWAS 5-8 .”

    From Identification of common genetic risk variants for autism spectrum disorder (2019) · cites this paper as [8]

  • A single common SNP has a very weak effect on ASD risk.

    “Common variation in the form of single-nucleotide polymorphisms (SNPs) has a very weak effect when a given SNP is considered individually (16).”

    From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [16]

  • ASD genomewide association studies have not identified reproducible SNP associations.

    “and have failed to identify reproducible SNP associations (16)(17)(18)(19)(20).”

    From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [16]

  • ASD genomewide association studies to date have been underpowered because individual SNPs have weak effects and sample sizes have been insufficient.

    “As a result, genomewide association studies carried out to date have been underpowered due to the weak effect of individual SNPs (16) and, hence, insufficient sample size [the largest study has analyzed 2,705 families (16)]”

    From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [16]

  • Polygenic risk from many SNPs is a major determinant of ASD variance.

    “However, polygenic risk due to a large number of SNPs is a major determinant of the variance for ASD (11,12,16) (Fig. 1).”

    From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [16]

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.

  • Two positions reported for rs1718101

    Minor

    Table 3 places rs1718101 at position 145753720, while Table 5 places the same SNP at 145753721.

  • Total family count differs between Discussion and Table 1

    Minor

    The Discussion says the combined analysis included 2678 families, but Table 1 lists 2705 spectrum families. The table identifies 2678 as the number of families with one case, not the total number of families.

  • Wang et al. attribution conflicts with Table 4 reference

    Minor

    The text attributes rs1328244 and rs6646569 to Wang et al. (22), but Table 4 gives (21) as the reference for their original P-values.

3 of 3

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Authors
Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, S., Bolton, P. F., Bourgeron, T., Brennan, S., Brian, J., Casey, J., Conroy, J., Correia, C., Corsello, C., Crawford, E. L., de Jonge, M., Delorme, R., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B. A., Folstein, S. E., Fombonne, E., Gilbert, J., Gillberg, C., Glessner, J. T., Green, A., Green, J., Guter, S. J., Heron, E. A., Holt, R., Howe, J. L., Hughes, G., Hus, V., Igliozzi, R., Jacob, S., Kenny, G. P., Kim, C., Kolevzon, A., Kustanovich, V., Lajonchere, C. M., Lamb, J. A., Law-Smith, M., Leboyer, M., Le Couteur, A., Leventhal, B. L., Liu, X.-Q., Lombard, F., Lord, C., Lotspeich, L., Lund, S. C., Magalhaes, T. R., Mantoulan, C., McDougle, C. J., Melhem, N. M., Merikangas, A., Minshew, N. J., Mirza, G. K., Munson, J., Noakes, C., Nygren, G., Papanikolaou, K., Pagnamenta, A. T., Parrini, B., Paton, T., Pickles, A., Posey, D. J., Poustka, F., Ragoussis, J., Regan, R., Roberts, W., Roeder, K., Roge, B., Rutter, M. L., Schlitt, S., Shah, N., Sheffield, V. C., Soorya, L., Sousa, I., Stoppioni, V., Sykes, N., Tancredi, R., Thompson, A. P., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J. B., Volkmar, F., Vorstman, J., Wallace, S., Wing, K., Wittemeyer, K., Wood, S., Zurawiecki, D., Zwaigenbaum, L., Bailey, A. J., Battaglia, A., Cantor, R. M., Coon, H., Cuccaro, M. L., Dawson, G., Ennis, S., Freitag, C. M., Geschwind, D. H., Haines, J. L., Klauck, S. M., McMahon, W. M., Maestrini, E., Miller, J., Monaco, A. P., Nelson, S. F., Nurnberger, J. I., Oliveira, G., Parr, J. R., Pericak-Vance, M. A., Piven, J., Schellenberg, G. D., Scherer, S. W., Vicente, A. M., Wassink, T. H., Wijsman, E. M., Betancur, C., Buxbaum, J. D., Cook, E. H., Gallagher, L., Gill, M., Hallmayer, J., Paterson, A. D., Sutcliffe, J. S., Szatmari, P., Vieland, V. J., Hakonarson, H., & Devlin, B.
Affiliations
  • Trinity College Dublin (IE)
  • University of Pittsburgh (US)
  • University of Toronto (CA)
  • Unidade Local de Saúde de Coimbra (PT)
  • University of Bologna (IT)
  • King's College London (GB)
  • Goethe University Frankfurt (DE)
  • Centre National de la Recherche Scientifique (FR)
  • University College Dublin (IE)
  • University of Lisbon (PT)
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  • Assistance Publique – Hôpitaux de Paris (FR)
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  • Centre for Human Genetics (GB)
  • Memorial University of Newfoundland (CA)
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  • Children's Hospital of Philadelphia (US)
  • University of Manchester (GB)
  • University of Illinois Chicago (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Autism Speaks (US)
  • Inserm (FR)
  • Nathan Kline Institute for Psychiatric Research (US)
  • University of Manitoba (CA)
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  • Université Toulouse - Jean Jaurès (FR)
  • Harvard University (US)
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  • Indiana University Bloomington (US)
  • Carnegie Mellon University (US)
  • McMaster University (CA)
  • National and Kapodistrian University of Athens (GR)
  • Centre for Addiction and Mental Health (CA)
  • Yale University (US)
  • Warneford Hospital (GB)
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  • University of British Columbia (CA)
  • University of California, Los Angeles (US)
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  • German Cancer Research Center (DE)
  • Tufts University (US)
  • Newcastle University (GB)
  • University of North Carolina at Chapel Hill (US)
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  • Battelle (US)
Corresponding author
  • Anney, Richard
  • Devlin, Bernie
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2012-07-26
Volume
21
Issue
21
Pages
4781-4792
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/dds301
PMC
PMC3471395
OpenAlex
W2100242214
Semantic Scholar
df88effa48e2bf8b1f92e97b9f661df36de39d9a
Cited by
375
References
69
Citations by year
2026: 9 · 2025: 6 · 2024: 10 · 2023: 14 · 2022: 12 · 2021: 23 · 2020: 30 · 2019: 25 · 2018: 24 · 2017: 38 · 2016: 38 · 2015: 41 · 2014: 55 · 2013: 43 · 2012: 4
FWCI
23.44
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • HAL (submittedVersion, other-oa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
  • eSpace (Curtin University) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by-nc)
  • UNC Libraries
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Autism Speaks (AS7569)
  • GlaxoSmithKline
  • Ontario Innovation Trust
  • Genome Canada
  • Wellcome Trust (075491, 075491/Z/04,, 090532)
  • Health Research Board
  • Ontario Genomics
  • Hussman Foundation
  • Fondation Orange
  • Ontario Genomics Institute
  • Sick Kids Foundation
  • National Institute for Health and Care Research (NF-SI-0510-10268)
  • Science Foundation Ireland
  • Deutsche Forschungsgemeinschaft
  • Institut National de la Santé et de la Recherche Médicale
  • Koninklijke Nederlandse Akademie van Wetenschappen
  • Ministero della Salute
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (825.06.031)
  • University of Toronto
  • Fondation de France
  • Hospital for Sick Children
  • National Institutes of Health (075491/Z/04, MH057881, HD055748, HD055751)
  • Canadian Institutes of Health Research
  • Medical Research Council
  • Ontario Ministry of Research and Innovation
  • National Institute of Mental Health (MH-066673, R01MH061009, MH66766, R01MH052708, U54MH066673, MH06359, R01MH094400, R01MH080647, R37MH057881, U10MH066766, MH 55284, MH081754, R01MH057881, R01MH081754, MH52708, MH080647, MH057881, MH061009, R01MH055284)
  • National Institute of Neurological Disorders and Stroke (NS026630, NS049261, P01NS026630, R01NS049261, R01NS042165, NS-042165)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD055751, P50HD055782, HD035469, HD055784, P01HD035469, HD055751, P50HD055748, P50HD055784, HD055782, HD 055748)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
autism spectrum disorder, common genetic variants, single nucleotide polymorphisms, genome-wide association study, CNTNAP2, language development, family transmission, genetic susceptibility
MeSH terms
Alleles, Child, Child Development Disorders, Pervasive, Female, Gene Frequency, Genotype, Humans, Language Development, Male, Membrane Proteins, Nerve Tissue Proteins, Risk Factors, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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