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Cited by 143Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalities

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

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IMGSAC, Maestrini, E, Pagnamenta, A T, Lamb, J A, Bacchelli, E, Sykes, N H, Sousa, I, Toma, C +17 more·2010·Molecular Psychiatry
DOI 10.1038/mp.2009.34PMC PMC2934739
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Abstract

Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family.

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  • 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 [18]

    The Discussion reports a replicated association for the DOCK4 SNP rs2217262 and suggests that a DOCK4 deletion may influence ASD susceptibility. The Results describe a duplication involving DOCK4, but the Discussion says duplications may not be damaging; this paper does not establish a duplication associated with ASD. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • DOCK4 is located at chromosome band 7q31.1, an autism-susceptible locus.

    “DOCK4 is located at chromosome band 7q31.1 18, 19, an autism-susceptible locus resided by several ASD-associated genes involved in development and language regulation.”

    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 [18]

    The Discussion identifies the IMMP2L/DOCK4 locus on chromosome 7 as a possible contributor to autism susceptibility, and the Introduction places the studied locus on chromosome 7q. Our copy does not specify that DOCK4 is at the narrower band 7q31.1, so that precise location is not verified. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Authors
IMGSAC, Maestrini, E., Pagnamenta, A. T., Lamb, J. A., Bacchelli, E., Sykes, N. H., Sousa, I., Toma, C., Barnby, G., Butler, H., Winchester, L., Scerri, T. S., Minopoli, F., Reichert, J., Cai, G., Buxbaum, J. D., Korvatska, O., Schellenberg, G. D., Dawson, G., Bildt, A. D., Minderaa, R. B., Mulder, E. J., Morris, A. P., Bailey, A. J., & Monaco, A. P.
Affiliations
  • University of Bologna (IT)
  • Centre for Human Genetics (GB)
  • Icahn School of Medicine at Mount Sinai (US)
  • VA Puget Sound Health Care System (US)
  • Autism Speaks (US)
  • University Medical Center Groningen (NL)
Corresponding author
  • Bailey, A J
  • Monaco, A P
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2009-04-28
Volume
15
Issue
9
Pages
954-968
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2009.34
PMC
PMC2934739
OpenAlex
W2121045992
Cited by
143
References
9
Citations by year
2026: 2 · 2025: 4 · 2024: 3 · 2023: 12 · 2022: 6 · 2021: 11 · 2020: 9 · 2019: 3 · 2018: 8 · 2017: 4 · 2016: 10 · 2015: 7 · 2014: 12 · 2013: 12 · 2012: 12
FWCI
6.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Simons Foundation
  • Nancy Lurie Marks Family Foundation
  • Sundhed og Sygdom, Det Frie Forskningsråd
  • Wellcome Trust (059091, 081682, 075491, 064890)
  • Deutsche Forschungsgemeinschaft
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • Università di Bologna
  • National Institutes of Health (5k02mh001389-03, MO1 RR06022, K02 MH01389)
  • Medical Research Council
  • National Institute of Mental Health (K05 MH01196, K02MH01389, K05MH001196)
  • National Center for Research Resources (M01RR006022, M01 RR-06022)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U19-HD 35482, U19HD035482)
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 › Genomic variations and chromosomal abnormalities
Keywords
autism spectrum disorder, IMMP2L, DOCK4, copy number variation, single nucleotide polymorphisms, genetic susceptibility, chromosome 7, linkage analysis
MeSH terms
Adult, Autistic Disorder, Child, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 7, Female, Genotype, Humans, Male, Endopeptidases, Genetic Variation, Linkage Disequilibrium, Gene Dosage, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, GTPase-Activating Proteins

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