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Original article
Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects
  1. J A Lamb1,
  2. G Barnby1,
  3. E Bonora1,*,
  4. N Sykes1,
  5. E Bacchelli2,
  6. F Blasi2,
  7. E Maestrini2,
  8. J Broxholme1,
  9. J Tzenova1,3,
  10. D Weeks4,
  11. A J Bailey5,
  12. A P Monaco1,
  13. the International Molecular Genetic Study of Autism Consortium (IMGSAC)
  1. 1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  2. 2University of Bologna, Dipartimento di Biologia Evoluzionistica Sperimentale and Laboratorio di Genetica Medica—Policlinico S.Orsola, Bologna, Italy
  3. 3Department of Cardiovascular Medicine, University of Oxford, Oxford, UK
  4. 4Department of Human Genetics, University of Pittsburgh, Pittsburgh, USA
  5. 5Section of Child and Adolescent Psychiatry, University Department of Psychiatry, Park Hospital for Children, Oxford, UK
  1. Correspondence to:
 Dr A P Monaco
 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK; anthony.monacowell.ox.ac.uk; A J Bailey, Section of Child and Adolescent Psychiatry, University Department of Psychiatry, Park Hospital for Children, Oxford, OX3 7LQ, UK; anthony.baileypsychiatry.ox.ac.uk

Abstract

Background and methods: Autism is a severe neurodevelopmental disorder, which has a complex genetic predisposition. The ratio of males to females affected by autism is approximately 4:1, suggesting that sex specific factors are involved in its development. We reported previously the results of a genomewide screen for autism susceptibility loci in 83 affected sibling pairs (ASP), and follow up analysis in 152 ASP. Here, we report analysis of an expanded sample of 219 ASP, using sex and parent of origin linkage modelling at loci on chromosomes 2, 7, 9, 15, and 16.

Results: The results suggest that linkage to chromosomes 7q and 16p is contributed largely by the male–male ASP (MLS = 2.55 v 0.12, and MLS = 2.48 v 0.00, for the 145 male–male and 74 male–female/female–female ASP on chromosomes 7 and 16 respectively). Conversely linkage to chromosome 15q appears to be attributable to the male–female/female–female ASP (MLS = 2.62 v 0.00, for non-male and male–male ASP respectively). On chromosomes 2 and 9, all ASP contribute to linkage. These data, supported by permutation, suggest a possible sex limited effect of susceptibility loci on chromosomes 7, 15, and 16. Parent of origin linkage modelling indicates two distinct regions of paternal and maternal identity by descent sharing on chromosome 7 (paternal MLS = 1.46 at ∼112 cM, and maternal MLS = 1.83 at ∼135 cM; corresponding maternal and paternal MLS = 0.53 and 0.28 respectively), and maternal specific sharing on chromosome 9 (maternal MLS = 1.99 at ∼30 cM; paternal MLS = 0.02).

Conclusion: These data support the possibility of two discrete loci underlying linkage of autism to chromosome 7, and implicate possible parent of origin specific effects in the aetiology of autism.

  • ADI-R, Autism Diagnostic Interview Revised
  • ADOS, Autism Diagnostic Observation Schedule
  • ADOS-G, Autism Diagnostic Observation Schedule Generic
  • ASP, affected sibling pairs
  • IBD, identity by descent
  • autistic disorder
  • genomic imprinting
  • linkage
  • parent of origin
  • sex limited

https://doi.org/10.1136/jmg.2004.025668

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    Footnotes

    • ↵* Present address: Unità di Genetica Medica, Policlinico S. Orsola, Bologna, Italy

    • Competing interests: none declared

    • The IMGSAC website is http://www.well.ox.ac.uk/~maestrin/iat.html. Members of the IMGSAC are as follows. UK: Section of Child and Adolescent Psychiatry, University Department of Psychiatry, Park Hospital for Children, Oxford: N Mathews, J Parr, S Wallace and A Bailey; Wellcome Trust Centre for Human Genetics, University of Oxford: G Barnby, E Bonora, J Lamb, A Marlow, N Sykes and A Monaco; Social, Genetic & Development Research Centre, Institute of Psychiatry, London: P Bolton and M Rutter; Newcomen Centre, Guy’s Hospital, London: G Baird; South East Thames Regional Genetics Centre, Division of Medical and Molecular Genetics, Guy’s Hospital, London: S Abbs, Z Docherty, C Ogilvie and P Warburton; School of Clinical Medical Sciences, University of Newcastle: T Berney, A Le Couteur and H McConachie; Developmental Psychiatry Section, University of Cambridge Clinical School: P de Vries and E Weisblatt; Academic Department of Child Psychiatry, University of Manchester: C Aldred, J-A Wilkinson and J Green; School of Epidemiology & Health Science, University of Manchester: A Pickles; European Collection of Cell Cultures, Health Protection Agency, Porton Down: P Bracegirdle, R Packer and B Bolton. Italy: University of Bologna, Dipartimento di Biologia Evoluzionistica Sperimentale, Bologna: E Bacchelli, F Blasi, S Carone and E Maestrini. The Netherlands: AZU, Department of Child and Adolescent Psychiatry, Utrecht: Maretha De Jonge, C Kemner, M Scherpenisse, K Steggehuis and H Van Engeland; Department of Child Psychiatry, Utrecht: I den Hartog. Germany: Deutsches Krebsforschungszentrum, Molecular Genome Analysis, Heidelberg: S M Klauck, B Felder, C Schuster and A Poustka; JW Goethe-Universität, Department of Child and Adolescent Psychiatry, Frankfurt: S Bölte, S Feineis-Matthews, N Uhlig, D Rühl, G Schmötzer and F Poustka. France: Hôpital la Grave, Toulouse: E Fombonne, J Fremolle-Kruck, C Mantoulan, K Wittemeyer and B Rogé. Denmark: Centre for Autisme, Bagsvaerd: E Ulsted Sorensen, B Viskum, R Cotterill, K Brondum-Nielsen, G Eriksen, D Haracopos, T Isager and L Pedersen. Greece: Agia Sophia Children’s Hospital, Athens: K Papanikolaou and J Tsiantis. USA: Departments of Human Genetics and Biostatistics, University of Pittsburgh Graduate School of Public Health: D Weeks; Department of Psychiatry, University of Chicago: J Salt, S Guter, B Leventhal and E Cook; UCLA Center for Neurobehavioural Genetics, Los Angeles: S Nelson and S Smalley; UCLA Psychiatric Institute, Child Psychiatry Division: J Levitt; University of Michigan Autism and Communicative Disorders Center, Ann Arbor: C Corsello and C Lord; Yale University, New Haven: J Bregman, A Klin, K Koenig, R Oti and F Volkmar.