CoChat
Sign Up
Cited by 11Autism Spectrum Disorder ResearchGenetic Associations and EpidemiologyGenetics and Neurodevelopmental Disorders

A Pooled Genome-Wide Association Study of Asperger Syndrome

Open access
Warrier, Varun, Chakrabarti, Bhismadev, Murphy, Laura, Chan, Allen, Craig, Ian, Mallya, Uma, Lakatošová, Silvia, Rehnstrom, Karola +5 more·2015·PLOS ONE
DOI 10.1371/journal.pone.0131202PMC PMC4503355
Open this paper in CoChat — free accountOpen PDF

Abstract

Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0131202

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Recent studies have identified DOCK4 variations associated with ASD, including single nucleotide variations and chromosome microdeletions or duplications.

    “Recent studies have identified a number of DOCK4 variations associated with ASD, including both single nucleotide variations (SNVs) and chromosome microdeletions or duplications (Supplementary Table 1) 18–26.”

    From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [23]

    The Discussion identifies an intronic DOCK4 SNP as nominally associated in the Asperger syndrome study, and the References list earlier work on DOCK4 deletions and copy-number variation in the IMMP2L–DOCK4 region. But the paper does not identify DOCK4 duplications specifically. It also reports that its SNP did not remain significant after correction or show a significant association in a larger autism-spectrum cohort. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

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

The self-check needs the paper’s full text.

Cites

No references could be resolved yet.

Research works printed but not linked: 30

  1. [1]American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. 4th edition Washington, DC: American Psychiatric Association; 1994.
  2. [2]Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, et al Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011; 68: 1095– 102. 10.1001/archgenpsychiatry.2011.76 21727249 PMC4440679 · DOI · Paper page
  3. [3]Persico AM, Napolioni V. Autism genetics. Behav Brain Res. 2013; 251: 95– 112. 10.1016/j.bbr.2013.06.012 23769996 · DOI
  4. [4]Baron-Cohen S, Scott FJ, Allison C, Williams J, Bolton P, Matthews FE, et al Prevalence of autism-spectrum conditions: UK school-based population study. Br J Psychiatry. 2009; 194: 500– 9. 10.1192/bjp.bp.108.059345 19478287 · DOI · Paper page
  5. [5]Lai M-C, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2013; 13: 61539– 1
  6. [6]Mbadiwe T, Millis RM. Epigenetics and Autism. Autism Res Treat. 2013; 2013: 826156. PMC3787640 24151554
  7. [7]Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet. 2005; 14: 483– 92. 15615769 PMC1224722
  8. [8]Bill BR, Geschwind DH. Genetic advances in autism: heterogeneity and convergence on shared pathways. Curr Opin Genet Dev. 2009; 19: 271– 8. 10.1016/j.gde.2009.04.004 19477629 PMC2715429 · DOI · Paper page
  9. [9]Geschwind DH. Advances in autism. Annu Rev Med. 2009; 60: 367– 80. 10.1146/annurev.med.60.053107.121225 19630577 PMC3645857 · DOI · Paper page
  10. [10]Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ, et al Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism. 2012; 3: 9 10.1186/2040-2392-3-9 23067556 PMC3579743 · DOI · Paper page
  11. [11]Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, et al Most genetic risk for autism resides with common variation. Nat Genet. 2014; 46: 881– 5. 10.1038/ng.3039 25038753 PMC4137411 · DOI · Paper page
  12. [12]Lai MC, Lombardo MV, Ecker C, Chakrabarti B, Suckling J, Bullmore ET, et al. Neuroanatomy of Individual Differences in Language in Adult Males with Autism. Cereb Cortex. 2014. [Epub ahead of print]. PMC4585508 25249409
  13. [13]Chakrabarti B, Dudbridge F, Kent L, Wheelwright S, Hill-Cawthorne G, Allison C, et al Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Autism Res. 2009; 2: 157– 77. 10.1002/aur.80 19598235 · DOI · Paper page
  14. [14]Szelinger S, Pearson JV, Craig DW. Microarray-based genome-wide association studies using pooled DNA. Methods Mol Bio. 2011; 700: 49– 60. 21204026
  15. [15]Butcher LM, Meaburn E, Liu L, Fernandes C, Hill L, Al-Chalabi A, et al Genotyping pooled DNA on microarrays: a systematic genome screen of thousands of SNPs in large samples to detect QTLs for complex traits. Behav Genet. 2004; 34: 549– 55. 15319578
  16. [16]Butcher LM, Meaburn E, Knight J, Sham PC, Schalkwyk LC, Craig IW, et al SNPs, microarrays and pooled DNA: identification of four loci associated with mild mental impairment in a sample of 6000 children. Hum Mol Genet. 2005; 4: 1315– 25. 15800012
  17. [17]Meaburn EL, Harlaar N, Craig IW, Schalkwyk LC, Plomin R. Quantitative trait locus association scan of early reading disability and ability using pooled DNA and 100K SNP microarrays in a sample of 5760 children. Mol Psychiatry. 2008; 13: 729– 40. 17684495
  18. [18]Davis OSP, Plomin R, Schalkwyk LC. The SNPMaP package for R: a framework for genome-wide association using DNA pooling on microarrays. Bioinformatics. 2009; 25: 281– 3. 10.1093/bioinformatics/btn587 19008252 PMC2639010 · DOI
  19. [19]Barratt BJ, Payne F, Rance HE, Nutland S, Todd JA, Clayton DG. Identification of the sources of error in allele frequency estimations from pooled DNA indicates an optimal experimental design. Ann Hum Genet. 2002; 66: 393– 405. 12485472
  20. [20]Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013; 381: 1371– 9 10.1016/S0140-6736(12)62129-1 23453885 PMC3714010 · DOI · Paper page
  21. [21]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81: 559– 75. 17701901 PMC1950838
  22. [22]Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40: D930– 4. 10.1093/nar/gkr917 22064851 PMC3245002 · DOI · Paper page
  23. [23]Chelala C, Khan A, Lemoine NR. SNPnexus: a web database for functional annotation of newly discovered and public domain single nucleotide polymorphisms. Bioinformatics, 2008; 25: 655– 661. 10.1093/bioinformatics/btn653 19098027 PMC2647830 · DOI
  24. [24]Schosser A, Pirlo K, Gaysina D, Cohen-Woods S, Schalkwyk LC, Elkin A, Korszun A, Gunasinghe C, Gray J, Jones L, Meaburn E, Farmer, AE, Craig IW, McGuffin P. Utility of the pooling approach as applied to whole genome association scans with high-density Affymetrix microarrays. BMC Res Notes. 2010; 3: 274 10.1186/1756-0500-3-274 21040578 PMC2984392 · DOI
  25. [25]Pagnamenta AT, Bacchelli E, de Jonge MV, Mirza G, Scerri TS, Minopoli F, et al Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia. Biol Psychiatry. 2010; 4: 320– 8 PMC2941017 20346443
  26. [26]Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I, et al High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Mol Psychiatry. 2010; 9: 954– 68. PMC2934739 19401682
  27. [27]Bartlett CW, Flax JF, Logue MW, Smith BJ, Vieland VJ, Tallal P, et al Examination of potential overlap in autism and language loci on chromosomes 2, 7, and 13 in two independent samples ascertained for specific language impairment. Hum Hered. 2004; 57: 10– 20. 15133308 PMC2976973
  28. [28]Talebizadeh Z, Arking DE, Hu VW. A Novel Stratification Method in Linkage Studies to Address Inter- and Intra-Family Heterogeneity in Autism. PloS One. 2013; 8: e67569 23840741 PMC3694043
  29. [29]Bartlett CW, Flax JF, Logue MW, Vieland VJ, Bassett AS, Tallal P, et al A major susceptibility locus for specific language impairment is located on 13q21. Am J Hum Genet. 2002; 71: 45– 55. 12048648 PMC384992
  30. [30]Tian C, Gregersen PK, Seldin MF. Accounting for ancestry: population substructure and genome-wide association studies. Hum Mol Genet. 2008; 17: R143– 50. 10.1093/hmg/ddn268 18852203 PMC2782357 · DOI

Cited by

Sorted by citations

Authors
Warrier, V., Chakrabarti, B., Murphy, L., Chan, A., Craig, I., Mallya, U., Lakatošová, S., Rehnstrom, K., Peltonen, L., Wheelwright, S., Allison, C., Fisher, S. E., & Baron-Cohen, S.
Affiliations
  • University of Cambridge (GB)
  • King's College London (GB)
  • Wellcome Sanger Institute (GB)
  • Radboud University Nijmegen (NL)
Corresponding author
Warrier, Varun
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2015-07-15
Volume
10
Issue
7
Pages
e0131202
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0131202
PMC
PMC4503355
OpenAlex
W1809937165
Cited by
11
References
0
Citations by year
2026: 1 · 2023: 1 · 2020: 2 · 2019: 2 · 2017: 3 · 2015: 2
FWCI
1.00
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CentAUR (University of Reading) (acceptedVersion, public-domain)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • Nancy Lurie Marks Family Foundation
  • Wellcome Trust
  • Cambridge Commonwealth Trust
  • Max-Planck-Gesellschaft
  • Medical Research Council
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Asperger syndrome, autism spectrum disorder, genetic susceptibility, single nucleotide polymorphisms, candidate loci, Psychiatric Genomics Consortium, neurodevelopmental disorders
MeSH terms
Female, Gene Frequency, Humans, Male, Genome, Human, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Asperger Syndrome, 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.

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