CoChat
Sign Up
Cited by 593Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersGenetic Associations and Epidemiology

A genome-wide scan for common alleles affecting risk for autism

Open access
Anney, R., Klei, L., Pinto, D., Regan, R., Conroy, J., Magalhaes, T. R., Correia, C., Abrahams, B. S. +158 more·2010·Human Molecular Genetics
DOI 10.1093/hmg/ddq307PMC PMC2947401
Open this paper in CoChat — free accountOpen PDF

Abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

AI snapshot

Written from the paper’s full text.

TL;DR

The Autism Genome Project genotyped 1558 ASD families for ~1 million SNPs and found one primary-analysis association crossing genome-wide significance: rs4141463 within MACROD2 in the strict-diagnosis, European-ancestry analysis (P = 2.1 × 10−8). Replication and combined analyses showed a smaller effect consistent with the winner’s curse, and exploratory subtype analyses yielded no associations surviving correction for multiple testing.

Key findings

  • In the AGP discovery sample, rs4141463 in MACROD2 crossed the P < 5 × 10−8 threshold in the strict diagnosis, European ancestry analysis: P = 2.1 × 10−8, OR = 0.56 (95% CI 0.47–0.67) for the minor allele.
  • In AGRE replication, the risk allele at rs4141463 was again over-transmitted but with a much smaller effect: OR = 0.84 (95% CI 0.67–1.04), P = 1.3 × 10−1; combined AGP + AGRE gave P = 4.7 × 10−8, OR = 0.65, and AGP + AGRE + SAGE gave P = 3.7 × 10−8, OR = 0.73.
  • Exploratory analyses found no association below 5 × 10−8 in AGP discovery alone; combined AGP + AGRE analyses crossed the threshold for rs3784730 in ST8SIA2, rs2196826 in PLD5, and rs9532931 in KIAA0564, but these would not be significant after correction for multiple testing.
  • Candidate-locus comparisons found some support for CNTNAP2, RELN, and SLC25A12 (P < 10−4) but did not garner additional evidence for the prior GWA loci at 5p14.1 (CDH9–CDH10) or 5p15.2 (SEMA5A–TAS2R1).

Methods

  • The AGP Consortium collected 1558 ASD families (4712 subjects) and genotyped them on the Illumina Human 1M-single Infinium BeadChip; after QC, 1369 families with 1385 ASD probands were analyzed. Diagnosis used ADI-R and ADOS, with strict versus spectrum classes and all-ancestry versus European-ancestry partitions.
  • Four primary family-based GWA analyses used an additive model: spectrum versus strict diagnosis by all versus European ancestry. Replication used 595 independent AGRE families (1086 probands), and control comparisons used 1965 SAGE control subjects; analyses combined family-based transmission data with AGRE mega-analysis and with SAGE controls via conditional logistic regression.
  • Exploratory analyses examined verbal/non-verbal status, IQ groups, and parent-of-origin effects, with family-based association methods including FBAT and an in-house program implementing Cordell et al. methods.

Limitations

  • The paper states that the sample size was relatively small for GWA studies (n ≤ 1369 families), limiting power to detect association and certainty of detected associations; detecting typical ORs of 1.1–1.3 would require many thousands of samples.
  • The paper states that winner’s curse and shrinkage to the mean could explain the smaller odds ratios estimated from replication data, and that exploratory findings would not be significant after correction for multiple testing of diagnostic groups and sub-phenotypes.
  • The paper notes a caveat for rs4150167 in TAF1C: although genotype clusters looked typical, the relatively common allele (≈0.98) was over-transmitted, a pattern consistent with poor genotyping quality.

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

Integrity signals

Registry

Crossref · 10.1093/hmg/ddq307

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 9 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Exploratory analyses yielded strong signals within KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

    “They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.”
    Quote in the paperNot a substantial claim
  • Findingown data

    None of the exploratory analyses detected association below P < 5 × 10−8 in the AGP discovery sample alone.

    “None of our exploratory analyses detected association below the threshold of 5 × 10−8 in the AGP discovery sample alone.”
    Quote in the paperSubstantial claim
  • Findingcitation

    The effect size at rs4141463 in the AGRE replication sample was much smaller than in the original AGP sample.

    “When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold.”
    • Also stated in: § Genome-wide SNP association: primary analyses · plain
      “Although the common allele is over-transmitted in both the original and AGRE data sets, the differential transmission as measured by the odds ratio is notably smaller for the latter, a result that is consistent with the winner's curse (22).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Göring H.H. Terwilliger J.D. Blangero J. Large upward bias in estimation of locus-specific effects from genomewide scans Am. J. Hum. Genet. 2001 69 1357 1369 doi:10.1086/324471 11593451 PMC1235546 source

      Not checked in the free run.

  • Findingown data

    The analysis found some support for prior candidate loci CNTNAP2, RELN and SLC25A12 (P < 10−4).

    “We found some support for several prior candidate loci, including CNTNAP2, RELN and SLC25A12 (P < 10−4), but our analysis did not garner additional evidence for either of the top findings from the prior GWA studies.”
    Quote in the paperSubstantial claim
  • Findingown data

    For the combined samples, the association signal at rs4141463 barely fell below the P < 5 × 10−8 threshold.

    “When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold.”
    • Also stated in: § Genome-wide SNP association: primary analyses · plain
      “For example, at rs4141463 (in MACROD2), the estimated odds ratio changed from 0.56 to 0.65 for the strict diagnosis (Table 2), European ancestry, resulting in a P-value of 4.7 × 10−8.”
    Quote in the paperSubstantial claim
  • May combine two claims. 11
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Findingown data

    In combined AGP and AGRE analyses, three associations crossed the P-value threshold: rs3784730 in ST8SIA2 for verbal individuals, rs2196826 in PLD5 for verbal individuals, and rs9532931 in KIAA0564 for maternal parent of origin.

    “Moreover, in a combined analysis of the AGP and AGRE data, we observe three associations that cross the P-value threshold: for verbal individuals, for SNPs rs3784730 (in ST8SIA2) and rs2196826 (in PLD5); and, for maternal parent of origin, rs9532931 (in a gene for an uncharacterized predicted protein KIAA0564).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When the sample was split by IQ (probands with IQ >80 and IQ <70), no P-value exceeded the genome-wide significance threshold and none met P < 1 × 10−6.

    “When we explored the impact of IQ on GWA results by splitting the sample by probands with IQ >80 and those with IQ <70, no P-value exceeded the threshold for GWA significance and none met criterion P < 1 × 10−6.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    The software SpectralGEM estimated five significant dimensions of ancestry.

    “The software used was SpectralGEM (48), which estimated five significant dimensions of ancestry (Supplementary Material, Fig. S1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Lee A.B. Luca D. Klei L. Devlin B. Roeder K. Discovering genetic ancestry using spectral graph theory Genet. Epidemiol. 2010 34 51 59 19455578 PMC4610359 source

      Not checked in the free run.

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

    Findingown data

    Dominant and recessive models did not contribute meaningfully to the results.

    “We do not present, here, the results for the dominant or recessive models because they did not contribute meaningfully to the results.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Subsequent clustering on the dimensions of ancestry resulted in six clusters: three clusters of European ancestry with n = 824, 353, and 87; and three clusters reflecting other major ancestral groups with n = 68, 54, and 35.

    “Subsequent clustering on the dimensions of ancestry resulted in six clusters: three clusters of European ancestry, with n = 824, 353 and 87; and three clusters reflecting other major ancestral groups, with n = 68, 54 and 35 (e.g. African and Asian); see also Supplementary Material, Figure S1.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Genome-wide association studies have highlighted two ASD risk loci: 5p14.1 between CDH9 and CDH10, and 5p15.2 between SEMA5A and TAS2R1.

    “genome-wide association (GWA) studies have highlighted two ASD risk loci: 5p14.1, between the neuronal cadherin loci CDH9 and CDH10 (20), and 5p15.2, between the semaphorin (SEMA5A) and bitter taste receptor (TAS2R1) genes (21).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Wang K. Zhang H. Ma D. Bucan M. Glessner J.T. Abrahams B.S. Salyakina D. Imielinski M. Bradfield J.P. Sleiman P.M. Common genetic variants on 5p14.1 associate with autism spectrum disorders Nature 2009 459 528 533 doi:10.1038/nature07999 19404256 PMC2943511 source

      Not checked in the free run.

    • cites [21] Weiss L.A. Arking D.E. Daly M.J. Chakravarti A. Gene Discovery Project of Johns Hopkins & the Autism Consortium A genome-wide linkage and association scan reveals novel loci for autism Nature 2009 461 802 808 doi:10.1038/nature08490 19812673 PMC2772655 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    All results spring from a relatively small sample size for GWA studies (n ≤ 1369 families), limiting power to detect association and the certainty of the associations detected.

    “All of these results spring from a relatively small sample size for GWA studies (n ≤ 1369 families), limiting both our power to detect association and the certainty of the associations detected.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The method to analyze control and family-based data builds on two related ideas: matched case-control analysis using conditional logistic regression and the natural connection between family-based analysis and conditional logistic regression of alleles found in probands and matched pseudo-controls.

    “The method to analyze control and family-based data (49) builds on two related ideas: matched case–control analysis using conditional logistic regression (e.g. 52) and the natural connection between family-based analysis and conditional logistic regression of alleles found in probands (the transmitted alleles) and matched pseudo-controls (formed from transmitted and un-transmitted alleles) (49).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] Crossett A. Kent B.P. Klei L. Ringquist R. Trucco M. Roeder K. Devlin B. Using ancestry matching to combine family-based and unrelated samples for genome-wide association studies Statist. Med. 2010 in press) PMC4629477 20862653 source

      Not checked in the free run.

    • cites [52] Luca D. Ringquist S. Klei L. Lee A.B. Gieger C. Wichmann H.E. Schreiber S. Krawczak M. Lu Y. Styche A. On the use of general control samples for genome-wide association studies: genetic matching highlights causal variants Am. J. Hum. Genet. 2008 82 453 463 doi:10.1016/j.ajhg.2007.11.003 18252225 PMC2427172 source

      Not checked in the free run.

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

    Study design and conductnone given

    In this final SNP-based edit, six more individuals had a genotype completion rate of <95%.

    “In this final SNP-based edit, six more individuals had a genotype completion rate of <95%.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Duplicates from four families were removed.

    “Duplicates from four families were removed.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The four principal analyses covered the extremes of phenotype and ancestry.

    “These four analyses covered the extremes of phenotype and ancestry.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Imputed genotypes for a SNP were retained only when none of the called genotypes were discrepant with the 1M genotypes.

    “imputed genotypes for an SNP were retained only when none of the called genotypes were discrepant with the 1M genotypes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 105 samples genotyped on both platforms are representative for assessing imputation accuracy.

  • May combine two claims.

    Study design and conductown data

    For rs4150167, visual inspection revealed typical genotype clusters, but the relatively common allele (≈0.98) is over-transmitted, a pattern consistent with poor genotyping quality.

    “A caveat about the data for this SNP is worth noting: visual inspection revealed typical genotype clusters, yet the relatively common allele (≈0.98) is over-transmitted, a pattern consistent with poor genotyping quality.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    19 families with large numbers of Mendelian errors were removed from the analysis.

    “19 families with large numbers of errors were removed from the analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Probands from 80 families were removed from the analysis because they either carried chromosomal abnormalities, exhibited chromosomal cell line artifacts, or had highly penetrant ASD CNVs based on literature reports.

    “probands from 80 families were removed because they either carried chromosomal abnormalities, exhibited chromosomal cell line artifacts or, based on literature reports, had highly penetrant ASD CNVs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Common variants rarely have a major impact on risk for any disorder, especially ASD, which is known to diminish reproductive success.

    “In contrast, common variants rarely have such an impact on risk for any disorder, especially one like ASD that is known to diminish reproductive success.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The fraction of complete genotypes per individual was required to be ≥95% over the autosomes; 27 samples fell below this criterion.

    “The fraction of complete genotypes per individual was required to be ≥95% over the autosomes; 27 samples fell below this criterion.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Studies identifying common variants affecting ASD risk have met with limited success.

    “To date, studies identifying common variants affecting ASD risk have met with limited success.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    After removing monomorphic SNPs or those with a genotyping completion rate <95%, 991,221 SNPs were retained.

    “We then removed monomorphic SNPs or those with a genotyping completion rate <95%. After this step, 991 221 SNPs were retained.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Following this QC step, 4304 genotyped individuals were retained for 1445 pedigrees.

    “Following this QC step, 4304 genotyped individuals were retained for 1445 pedigrees.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Comparisons of the in-house program to FBAT results, when appropriate, yielded excellent agreement.

    “Comparisons of the in-house program to FBAT results, when appropriate, yielded excellent agreement (unpublished data).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Following the imputation QC process, each sample from the AGRE data set contained genotypes from the HapMap550 and 248,642 additional imputed genotypes for subsequent analysis.

    “Following this QC process, each sample from the AGRE data set contained genotypes from the HapMap550 and 248 642 additional imputed genotypes for subsequent analysis.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    For the figures in the manuscript, the more stringent criterion for genotyping completion rate more accurately reflects the final results after manual inspection of genotype clusters.

    “However, for the figures in the manuscript, we use the more stringent criterion for genotyping completion rate, which more accurately reflects the final results after manual inspection of genotype clusters.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Using a genotyping completion rate of 95% or more allows some SNPs of poor genotyping quality to enter the analysis; using a more stringent completion rate such as 99% removes low-quality SNPs at the cost of removing some high-quality SNPs.

    “We note that using a genotyping completion rate of 95% or more allows some SNPs of poor genotyping quality to enter the analysis; the alternative is to use a more stringent completion rate, such as 99%, which has the advantage of removing low-quality SNPs at the cost of removing some high-quality SNPs.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    Even if a common variant has only a small impact on individual risk, its population attributable risk could be substantial because it is carried by many individuals.

    “Nonetheless, even if a common variant has only a small impact on individual risk, its population attributable risk could be substantial because it is carried by many individuals.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    Following this QC step, there were 842,348 SNPs available for association analysis.

    “Following this QC step, there were 842 348 SNPs available for association analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Specific SNPs were eliminated based on genotypes in the homogeneous European cluster: 5499 were monomorphic; 2102 for completion rate <95%; 132,894 for MAF <0.01; 7734 for HWE P < 0.005; and 89 for Fst > 0.02.

    “Specific SNPs were eliminated on the basis of the genotypes in this homogeneous European cluster for the following reasons: 5499 were monomorphic; 2102 for completion rate <95%; 132 894 for MAF <0.01; 7734 for HWE P < 0.005; and 89 for Fst > 0.02.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The major European cluster (n = 824) is homogeneous and suitable for determining minor allele frequencies, Hardy–Weinberg equilibrium, and Wright's Fst.
27 of 27

  • The authors state this as an assumption.

    Level of function, as measured by IQ, is a major source of etiological heterogeneity for autism.

    “Level of function, as measured by IQ, has been assumed to be a major source of etiological heterogeneity for autism.”

  • The authors state this as an assumption.

    Microscopic and submicroscopic CNVs have a major and sometimes causal impact on risk for ASD.

    “These microscopic and submicroscopic CNVs are presumed to have a major and sometimes causal impact on risk for ASD.”

  • The paper relies on this without support.

    The 105 samples genotyped on both platforms are representative for assessing imputation accuracy.

    “a small set of 105 samples that were genotyped on both platforms and yielded high-quality genotypes”

  • The paper relies on this without support.

    The major European cluster (n = 824) is homogeneous and suitable for determining minor allele frequencies, Hardy–Weinberg equilibrium, and Wright's Fst.

    “The major European cluster (n = 824) was used to determine minor allele frequencies (MAFs), to evaluate Hardy–Weinberg equilibrium (HWE) and Wright's Fst among the genotyping sites.”
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?

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.

  • Reported mega-analysis family count conflicts with Table 1

    Minor

    The text says the AGP-AGRE mega-analysis used 2,179 families, but Table 1 reports 1,887 combined families for its largest primary-analysis group. Even the separate AGP and AGRE counts in that row total only 1,964 families.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. 2006, Nature genetics, 39, 25

Cited by

Sorted by citations

Related

Authors
Anney, R., Klei, L., Pinto, D., Regan, R., Conroy, J., Magalhaes, T. R., Correia, C., Abrahams, B. S., Sykes, N., Pagnamenta, A. T., Almeida, J., Bacchelli, E., Bailey, A. J., Baird, G., Battaglia, A., Berney, T., Bolshakova, N., Bolte, S., Bolton, P. F., Bourgeron, T., Brennan, S., Brian, J., Carson, A. R., Casallo, G., Casey, J., Chu, S. H., Cochrane, L., Corsello, C., Crawford, E. L., Crossett, A., Dawson, G., de Jonge, M., Delorme, R., Drmic, I., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B. A., Folstein, S. E., Fombonne, E., Freitag, C. M., Gilbert, J., Gillberg, C., Glessner, J. T., Goldberg, J., Green, J., Guter, S. J., Hakonarson, H., Heron, E. A., Hill, M., Holt, R., Howe, J. L., Hughes, G., Hus, V., Igliozzi, R., Kim, C., Klauck, S. M., Kolevzon, A., Korvatska, O., Kustanovich, V., Lajonchere, C. M., Lamb, J. A., Laskawiec, M., Leboyer, M., Le Couteur, A., Leventhal, B. L., Lionel, A. C., Liu, X.-Q., Lord, C., Lotspeich, L., Lund, S. C., Maestrini, E., Mahoney, W., Mantoulan, C., Marshall, C. R., McConachie, H., McDougle, C. J., McGrath, J., McMahon, W. M., Melhem, N. M., Merikangas, A., Migita, O., Minshew, N. J., Mirza, G. K., Munson, J., Nelson, S. F., Noakes, C., Noor, A., Nygren, G., Oliveira, G., Papanikolaou, K., Parr, J. R., Parrini, B., Paton, T., Pickles, A., Piven, J., Posey, D. J., Poustka, A., Poustka, F., Prasad, A., Ragoussis, J., Renshaw, K., Rickaby, J., Roberts, W., Roeder, K., Roge, B., Rutter, M. L., Bierut, L. J., Rice, J. P., Salt, J., Sansom, K., Sato, D., Segurado, R., Senman, L., Shah, N., Sheffield, V. C., Soorya, L., Sousa, I., Stoppioni, V., Strawbridge, C., Tancredi, R., Tansey, K., Thiruvahindrapduram, B., Thompson, A. P., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J. B., Volkmar, F., Wallace, S., Wang, K., Wang, Z., Wassink, T. H., Wing, K., Wittemeyer, K., Wood, S., Yaspan, B. L., Zurawiecki, D., Zwaigenbaum, L., Betancur, C., Buxbaum, J. D., Cantor, R. M., Cook, E. H., Coon, H., Cuccaro, M. L., Gallagher, L., Geschwind, D. H., Gill, M., Haines, J. L., Miller, J., Monaco, A. P., Nurnberger, J. I., Paterson, A. D., Pericak-Vance, M. A., Schellenberg, G. D., Scherer, S. W., Sutcliffe, J. S., Szatmari, P., Vicente, A. M., Vieland, V. J., Wijsman, E. M., Devlin, B., Ennis, S., & Hallmayer, J.
Affiliations
  • Trinity College Dublin (IE)
  • University of Pittsburgh (US)
  • University of Toronto (CA)
  • University College Dublin (IE)
  • University of Lisbon (PT)
  • University of California, Los Angeles (US)
  • Centre for Human Genetics (GB)
  • Unidade Local de Saúde de Coimbra (PT)
  • University of Bologna (IT)
  • Warneford Hospital (GB)
  • Guy's Hospital (GB)
  • Newcastle University (GB)
  • Centre National de la Recherche Scientifique (FR)
  • Carnegie Mellon University (US)
  • University of Michigan (US)
  • Vanderbilt University (US)
  • Autism Speaks (US)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Goethe University Frankfurt (DE)
  • Memorial University of Newfoundland (CA)
  • Children's Hospital of Philadelphia (US)
  • University of Iowa (US)
  • Inserm (FR)
  • Nathan Kline Institute for Psychiatric Research (US)
  • Stanford Medicine (US)
  • McMaster University (CA)
  • Université Toulouse - Jean Jaurès (FR)
  • Indiana University Indianapolis (US)
  • University of Utah (US)
  • Centre for Addiction and Mental Health (CA)
  • University of Manchester (GB)
  • University of North Carolina at Chapel Hill (US)
  • Washington University in St. Louis (US)
  • National and Kapodistrian University of Athens (GR)
  • Yale University (US)
  • University of Alberta (CA)
  • University of Pennsylvania (US)
  • Nationwide Children's Hospital (US)
  • University of Washington (US)
Corresponding author
Devlin, B.
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2010-07-27
Volume
19
Issue
20
Pages
4072-4082
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddq307
PMC
PMC2947401
OpenAlex
W2152157708
Semantic Scholar
3a96d1b538a3cddfcc7c17e0b67b0a504b8bdbfe
Cited by
593
References
53
Citations by year
2026: 14 · 2025: 10 · 2024: 15 · 2023: 17 · 2022: 18 · 2021: 26 · 2020: 35 · 2019: 44 · 2018: 27 · 2017: 35 · 2016: 41 · 2015: 51 · 2014: 71 · 2013: 63 · 2012: 59
FWCI
36.66
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Human Molecular Genetics (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, other-oa)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • HAL (submittedVersion, other-oa)
  • Research Repository UCD (University College Dublin) (submittedVersion, cc-by-nc-nd)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
  • Arrow@dit (Dublin Institute of Technology) (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)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by-nc)
  • Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by-nc)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • UNC Libraries
Funders
  • Howard Hughes Medical Institute
  • Autism Speaks (AS7462)
  • GlaxoSmithKline
  • Johns Hopkins University (HHSN268200782096C)
  • Ontario Innovation Trust
  • Genome Canada
  • Wellcome Trust (075491/Z/04 UK, 075491, 075491/Z/04,)
  • Health Research Board
  • Ontario Genomics
  • Hussman Foundation
  • Fondation FondaMental
  • Fondation Orange
  • Ontario Genomics Institute
  • Sick Kids Foundation
  • 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, HHSN268200782096C, AA008401, MH057881, CA089392, HD055751)
  • Canadian Institutes of Health Research
  • Medical Research Council (HHSN268200782096C)
  • Ontario Ministry of Research and Innovation
  • National Institute on Alcohol Abuse and Alcoholism (AA008401, U10AA008401)
  • National Institute of Mental Health (MH-066673, R01MH061009, MH66766, K01MH077930, R01MH052708, U54MH066673, MH06359, R01MH080647, R37MH057881, U10MH066766, MH077930, MH 55284, MH081754, R01MH057881, R01MH081754, MH52708, MH080647, MH057881, MH061009, R01MH055284, T32MH065215)
  • National Institute on Drug Abuse (FSCD; R01 DA013423, COGA; U10 AA008401, R01DA019963, R01DA013423, HHSN268200782096C, COGEND; P01 CA089392, DA013423)
  • National Human Genome Research Institute (U01HG004422, U01HG004446, U01HG004438)
  • National Cancer Institute (P01CA089392)
  • 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, HD055784, HD055751, P01HD035465, U19HD035469, P50HD055784, HD055782, HD35465)
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, genome-wide association study, MACROD2, winner's curse, copy number variation, ST8SIA2
MeSH terms
Alleles, Autistic Disorder, Genotype, Humans, Risk Factors, Genetic Variation, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Databases, Genetic, White People, Genome-Wide Association Study, DNA Copy Number Variations

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.

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 ›

Are you an author, or do you see a problem with this page? Request a review