Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mapping autism risk loci using genetic linkage and chromosomal rearrangements

A Corrigendum to this article was published on 01 October 2007

This article has been updated

Abstract

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12–p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Linkage across the genome for all families and ancestries, based on levels of diagnostic certainty.
Figure 2: Chromosome ideogram depicting 253 inferred CNVs found in 196 individuals with ASDs.
Figure 3: Highlighted linkage results due to removing families in which affected individuals carry putative CNVs.
Figure 4: Linkage peaks by male-only versus female-containing families, based on levels of diagnostic certainty.
Figure 5: The effect on linkage of splitting families into female-containing and male-only families while also removing families in which affected individuals putatively carry CNVs.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

Change history

  • 26 September 2007

    In the version of this article initially published, Kacie J. Meyer (University of Iowa, Iowa City) was inadvertently omitted from the author list, and the names of three authors (Frederieke Koop, Marjolein Langemeijer and Channa Hijmans) were misspelled. There were also minor errors in the abstract (“1,168 families” should read “1,181 families”) and in the final paragraph of the Discussion (“11q13–12” should read “11p13–12”). These errors have been corrected in the HTML and PDF versions of the article.

References

  1. American Psychological Association. Diagnostic and Statistical Manual of Mental Disorders (American Psychological Association, Washington, D.C., 1994).

  2. Chakrabarti, S. & Fombonne, E. Pervasive developmental disorders in preschool children: confirmation of high prevalence. Am. J. Psychiatry 162, 1133–1141 (2005).

    Article  Google Scholar 

  3. Veenstra-Vanderweele, J., Christian, S.L. & Cook, E.H., Jr. Autism as a paradigmatic complex genetic disorder. Annu. Rev. Genomics Hum. Genet. 5, 379–405 (2004).

    Article  CAS  Google Scholar 

  4. Xu, J., Zwaigenbaum, L., Szatmari, P. & Scherer, S.W. Molecular cytogenetics of autism. Curr. Genomics 5, 347–364 (2004).

    Article  CAS  Google Scholar 

  5. Bailey, A. et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25, 63–77 (1995).

    Article  CAS  Google Scholar 

  6. Piven, J. The broad autism phenotype: a complementary strategy for molecular genetic studies of autism. Am. J. Med. Genet. 105, 34–35 (2001).

    Article  CAS  Google Scholar 

  7. Jones, M.B. & Szatmari, P. Stoppage rules and genetic studies of autism. J. Autism Dev. Disord. 18, 31–40 (1988).

    Article  CAS  Google Scholar 

  8. Ritvo, E.R. et al. The UCLA-University of Utah epidemiologic survey of autism: prevalence. Am. J. Psychiatry 146, 194–199 (1989).

    Article  CAS  Google Scholar 

  9. Hallmayer, J. et al. On the twin risk in autism. Am. J. Hum. Genet. 71, 941–946 (2002).

    Article  Google Scholar 

  10. Pickles, A. et al. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am. J. Hum. Genet. 57, 717–726 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Risch, N. et al. A genomic screen of autism: evidence for a multilocus etiology. Am. J. Hum. Genet. 65, 493–507 (1999).

    Article  CAS  Google Scholar 

  12. Schellenberg, G.D. et al. Evidence for genetic linkage of autism to chromosomes 7 and 4. Mol. Psychiatry 11, 979 (2006).

    Article  CAS  Google Scholar 

  13. Freitag, C.M. The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol. Psychiatry 12, 2–22 (2007).

    Article  CAS  Google Scholar 

  14. Jamain, S. et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34, 27–29 (2003).

    Article  CAS  Google Scholar 

  15. Laumonnier, F. et al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am. J. Hum. Genet. 74, 552–557 (2004).

    Article  CAS  Google Scholar 

  16. Chubykin, A.A. et al. Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism. J. Biol. Chem. 280, 22365–22374 (2005).

    Article  CAS  Google Scholar 

  17. Durand, C.M. et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39, 25–27 (2007).

    Article  CAS  Google Scholar 

  18. Risi, S. et al. Combining information from multiple sources in the diagnosis of autism spectrum disorders. J. Am. Acad. Child Adolesc. Psychiatry 45, 1094–1103 (2006).

    Article  Google Scholar 

  19. Kong, X. et al. A combined linkage-physical map of the human genome. Am. J. Hum. Genet. 75, 1143–1148 (2004).

    Article  CAS  Google Scholar 

  20. Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247 (1995).

    Article  CAS  Google Scholar 

  21. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 445–454 (2006).

    Article  Google Scholar 

  22. Persico, A.M. & Bourgeron, T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 29, 349–358 (2006).

    Article  CAS  Google Scholar 

  23. Feng, J. et al. High frequency of neurexin 1β signal peptide structural variants in patients with autism. Neurosci. Lett. 409, 10–13 (2006).

    Article  CAS  Google Scholar 

  24. de Vries, B.B. et al. Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet. 77, 606–616 (2005).

    Article  CAS  Google Scholar 

  25. Sharp, A.J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat. Genet. 38, 1038–1042 (2006).

    Article  CAS  Google Scholar 

  26. Houlden, H. & Reilly, M.M. Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease. Neuromolecular Med. 8, 43–62 (2006).

    Article  CAS  Google Scholar 

  27. Potocki, L. et al. Molecular mechanism for duplication 17p11.2, the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat. Genet. 24, 84–87 (2000).

    Article  CAS  Google Scholar 

  28. Moog, U. et al. Hereditary motor and sensory neuropathy (HMSN) IA, developmental delay and autism related disorder in a boy with duplication (17)(p11.2p12). Genet. Couns. 15, 73–80 (2004).

    CAS  PubMed  Google Scholar 

  29. Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).

    Article  CAS  Google Scholar 

  30. Lamb, J.A. et al. Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects. J. Med. Genet. 42, 132–137 (2005).

    Article  CAS  Google Scholar 

  31. Stone, J.L. et al. Evidence for sex-specific risk alleles in autism spectrum disorder. Am. J. Hum. Genet. 75, 1117–1123 (2004).

    Article  CAS  Google Scholar 

  32. Falconer, D.S. Introduction to Quantitative Genetics (Longman, London, 1981).

    Google Scholar 

  33. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  34. Camp, N.J. & Farnham, J.M. Correcting for multiple analyses in genomewide linkage studies. Ann. Hum. Genet. 65, 577–582 (2001).

    Article  CAS  Google Scholar 

  35. Lange, C. & Laird, N.M. On a general class of conditional tests for family-based association studies in genetics: the asymptotic distribution, the conditional power, and optimality considerations. Genet. Epidemiol. 23, 165–180 (2002).

    Article  Google Scholar 

  36. Graf, E.R., Zhang, X., Jin, S.X., Linhoff, M.W. & Craig, A.M. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119, 1013–1026 (2004).

    Article  CAS  Google Scholar 

  37. Varoqueaux, F. et al. Neuroligins determine synapse maturation and function. Neuron 51, 741–754 (2006).

    Article  CAS  Google Scholar 

  38. Purcell, A.E., Jeon, O.H., Zimmerman, A.W., Blue, M.E. & Pevsner, J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57, 1618–1628 (2001).

    Article  CAS  Google Scholar 

  39. Shinohe, A. et al. Increased serum levels of glutamate in adult patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 1472–1477 (2006).

    Article  CAS  Google Scholar 

  40. Kugler, P. & Schleyer, V. Developmental expression of glutamate transporters and glutamate dehydrogenase in astrocytes of the postnatal rat hippocampus. Hippocampus 14, 975–985 (2004).

    Article  CAS  Google Scholar 

  41. Belmonte, M.K. & Bourgeron, T. Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat. Neurosci. 9, 1221–1225 (2006).

    Article  CAS  Google Scholar 

  42. Tavazoie, S.F., Alvarez, V.A., Ridenour, D.A., Kwiatkowski, D.J. & Sabatini, B.L. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat. Neurosci. 8, 1727–1734 (2005).

    Article  CAS  Google Scholar 

  43. Jalil, M.A. et al. Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier. J. Biol. Chem. 280, 31333–31339 (2005).

    Article  CAS  Google Scholar 

  44. O'Connell, J.R. & Weeks, D.E. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am. J. Hum. Genet. 63, 259–266 (1998).

    Article  CAS  Google Scholar 

  45. Rinaldo, A. et al. Characterization of multilocus linkage disequilibrium. Genet. Epidemiol. 28, 193–206 (2005).

    Article  Google Scholar 

  46. Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

    Article  CAS  Google Scholar 

  47. McPeek, M.S., Wu, X. & Ober, C. Best linear unbiased allele-frequency estimation in complex pedigrees. Biometrics 60, 359–367 (2004).

    Article  Google Scholar 

  48. Gudbjartsson, D.F., Jonasson, K., Frigge, M.L. & Kong, A. Allegro, a new computer program for multipoint linkage analysis. Nat. Genet. 25, 12–13 (2000).

    Article  CAS  Google Scholar 

  49. McQueen, M.B., Blacker, D. & Laird, N.M. Variance calculations for identity-by-descent estimation. Am. J. Hum. Genet. 78, 914–921 (2006).

    Article  CAS  Google Scholar 

  50. Li, C. & Wong, W.H. DNA-chip analyzer (dChip). in The Analysis of Gene Expression Data: Methods and Software (eds. Parmigiani, G., Garrett, E.S., Irizarry, R. & Zeger, S.L.) (Springer, New York, 2001).

    Google Scholar 

Download references

Acknowledgements

The authors are indebted to the participating families for their contribution of time and effort in support of this study. We gratefully acknowledge Autism Speaks, formerly the National Alliance for Autism Research, for financial support for data pooling, SNP genotyping and data analysis.

The Autism Genetics Cooperative thanks Assistance Publique-Hôpitaux de Paris, Canadian Institutes for Health Research (CIHR grant 11350 to P.S.), Catherine and Maxwell Meighan Foundation, Fondation de France, Fondation France Télécom, Fondation pour la Recherche Médicale, Genome Canada/Ontario Genomics Institute, The Hospital for Sick Children Foundation, Howard Hughes Medical Institute, INSERM, McLaughlin Centre for Molecular Medicine, National Institute of Child Health and Human Development, National Institute of Mental Health (MH066673 to J.D.B.; MH55135 to S.E.F.; MH52708 to N. Risch (University of California, San Francisco); MH061009 to J.S.S.), National Institute of Neurological Disorders and Stroke (NS042165 to J.H.; NS026630 and NS036738 to M.A.P.-V.; NS049261 to J.S.S.; NS043550 to T.H.W.), Swedish Science Council, Seaver Autism Research Foundation and The Centre for Applied Genomics (Toronto). S.W.S. is an Investigator of the CIHR and an HHMI International Scholar.

The Autism Genetic Resource Exchange Consortium gratefully acknowledges the resources provided by the participating families. The Autism Genetic Resource Exchange is a program of Cure Autism Now and is supported, in part, by the National Institute of Mental Health (MH64547 to D.H.G.).

The Collaborative Programs of Excellence thank the National Center for Research Resources (M01-RR00064), National Institute of Child Health and Human Development (U19HD34565 G.D. and G.S.), NIMH (MH057881), NINDS (5 U19 HD035476 to W.M.McM.) and the Utah Autism Foundation.

The International Molecular Genetic Study of Autism Consortium thanks the UK Medical Research Council, Wellcome Trust, BIOMED 2 (CT-97-2759), EC Fifth Framework (QLG2-CT-1999-0094), Telethon-Italy (GGP030227), Janus Korczak Foundation, Deutsche Forschungsgemeinschaft, Fondation France Telecom, Conseil Regional Midi-Pyrenees, Danish Medical Research Council, Sofiefonden, Beatrice Surovell Haskells Fond for Child Mental Health Research of Copenhagen, Danish Natural Science Research Council (9802210) and the US National Institutes of Health (U19 HD35482, MO1 RR06022, K05 MH01196, K02 MH01389). A.J.B. is the Cheryl and Reece Scott Professor of Psychiatry. A.P.M. is a Wellcome Trust Principal Research Fellow.

Requests for data or methods should be addressed to B.D. (devlinbj@upmc.edu) or S.W.S. (steve@genet.sickkids.on.ca).

Author information

Authors and Affiliations

Consortia

Contributions

P.S., A.D.P., S.W.S., V.J.V., M.A.P.-V., C.B., J.D.B., J.H., J.S.S., J.H., J.L.H., J.P., T.H.W., D.H.G., R.C., S.N., G.D., G.D.S., B.D., W.M.M., E.M.W., A.J.B., A.P.M. and E.H.C. were lead AGP investigators and contributed equally to this project.

The Autism Genome Project (AGP). The AGP comprises four existing consortia of partners or countries (listed alphabetically below).

Autism Genetics Cooperative. Canagen: P.S., A.D.P., L.Z., W.R., J.B., X.-Q.L., J.B.V., J.L.S., A.P.T., L.S., L.F., C.Q., S.E.B., M.B.J., C.R.M. and S.W.S. Iowa Data Coordinating Center: V.J.V., C.B., L.V.M., R.G. and A.S. University of Miami: M.A.P.-V., M.L.C. and J.R.G. University of South Carolina: H.H.W., R.K.A. Paris Autism Research: International Sibpair Study: C.B., T.B., C.G. and M.L. Seaver Autism Research Center: J.D.B., K.L.D., E.H. and J.M.S. Stanford University: J.H. and L.L. Vanderbilt University: J.S.S., J.L.H. and S.E.F. University of North Carolina/University of Iowa: J.P., T.H.W., K.J.M. and V.S.

The Autism Genetic Resource Exchange Consortium. D.H.G., M.B., W.T.B., R.M.C., J.N.C., T.C.G., M.H., C.LaJ., D.H.L., C.L.-M., J.M., S.N. C.A.S.-S., S.S., M.S. and R.E.T.

The Collaborative Programs of Excellence in Autism. H.C., G.D., B.D., A.E., P.F., L.K., W.M.McM., N.M., J.M., E.K., P.M.R., G.D.S., M.S., M.A.S., C.S., P.G.T., E.M.W. and C.-E.Y.

The International Molecular Genetic Study of Autism Consortium. France: B.R., C.M., K.W. and M.T. Germany: A.P., B.F., S.M.K., C.S., F.P., S.B., S.F.-M., E.H. and G.S. Greece: J.T., K.P. Italy: E.M., E.B., F.B., S.C. and C.T. The Netherlands: H.V.E., M. de J., C.K., F.K., M.L., C.H. and W.G.S. UK: G.B., P.F.B., M.L.R., E.W., J.G., C.A., J.-A.W., A.P., A.LeC., T.B., H.McC., A.J.B., K.F., G.H., A.H., J.R.P., S.W., A.P.M., G.B., K.K., J.A.L., I.S. and N.S. USA: E.H.C., S.J.G., B.L.L., J.S., C.L., C.C., V.H., D.E.W. and F.V. Canada: E.F.

Scientific management. A.S.

Corresponding authors

Correspondence to Stephen W Scherer or Bernie Devlin.

Ethics declarations

Competing interests

The author declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Binned size distribution of CNVs in batch, plate and filtered analyses. (PDF 93 kb)

Supplementary Fig. 2

Linkage results due to removing families in which affected individuals putatively carry CNV. (PDF 157 kb)

Supplementary Fig. 3

Principal component plot used to infer ancestry. (PDF 188 kb)

Supplementary Fig. 4

Linkage results obtained by analyzing families inferred to be of homogeneous European ancestry. (PDF 696 kb)

Supplementary Table 1

List of 624 CNVs in filtered analysis. (PDF 64 kb)

Supplementary Table 2

List of 254 CNVs in affected individuals. (PDF 380 kb)

Supplementary Table 3

Breakdown of CNVs in affected individuals. (PDF 325 kb)

Supplementary Table 4

List of validated CNVs. (PDF 926 kb)

Supplementary Methods (PDF 61 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

The Autism Genome Project Consortium. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39, 319–328 (2007). https://doi.org/10.1038/ng1985

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1985

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing