Original Article

Molecular Psychiatry advance online publication 28 April 2009; doi: 10.1038/mp.2009.34

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
MPOpen

E Maestrini1,11, A T Pagnamenta2,11, J A Lamb2,3,11, E Bacchelli1, N H Sykes2, I Sousa2, C Toma1, G Barnby2, H Butler2, L Winchester2, T S Scerri2, F Minopoli1, J Reichert4, G Cai4, J D Buxbaum4, O Korvatska5, G D Schellenberg6, G Dawson7,8, A de Bildt9, R B Minderaa9, E J Mulder9, A P Morris2, A J Bailey10 and A P Monaco2 IMGSAC12

  1. 1Department of Biology, University of Bologna, Bologna, Italy
  2. 2The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  3. 3Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK
  4. 4Department of Psychiatry, Seaver Autism Research Center, Mount Sinai School of Medicine, New York, NY, USA
  5. 5Geriatric Research Education and Clinical Centre, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA, USA
  6. 6Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
  7. 7Autism Speaks, New York, NY, USA
  8. 8Department of Psychology, University of Washington, Seattle, WA, USA
  9. 9Department of Psychiatry, Child and Adolescent Psychiatry, University Medical Center Groningen, Groningen, The Netherlands
  10. 10University Department of Psychiatry, Warneford Hospital, Oxford, UK

Correspondence: Professor AP Monaco, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. E-mail: anthony.monaco@well.ox.ac.uk; Professor AJ Bailey, University Department of Psychiatry, Warneford Hospital, Headington, Oxford OX3 7JX, UK. E-mail: Anthony.Bailey@psych.ox.ac.uk

11These authors contributed equally to this work.

12IMGSAC: see list of authors in Supplementary Information.

Received 20 October 2008; Revised 19 February 2009; Accepted 2 April 2009; Published online 28 April 2009.

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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.

Keywords:

autistic disorder, disease susceptibility, single nucleotide polymorphisms, linkage disequilibrium, chromosome 7, chromosome 2

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