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.
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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
American Psychological Association. Diagnostic and Statistical Manual of Mental Disorders (American Psychological Association, Washington, D.C., 1994).
Chakrabarti, S. & Fombonne, E. Pervasive developmental disorders in preschool children: confirmation of high prevalence. Am. J. Psychiatry 162, 1133–1141 (2005).
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).
Xu, J., Zwaigenbaum, L., Szatmari, P. & Scherer, S.W. Molecular cytogenetics of autism. Curr. Genomics 5, 347–364 (2004).
Bailey, A. et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25, 63–77 (1995).
Piven, J. The broad autism phenotype: a complementary strategy for molecular genetic studies of autism. Am. J. Med. Genet. 105, 34–35 (2001).
Jones, M.B. & Szatmari, P. Stoppage rules and genetic studies of autism. J. Autism Dev. Disord. 18, 31–40 (1988).
Ritvo, E.R. et al. The UCLA-University of Utah epidemiologic survey of autism: prevalence. Am. J. Psychiatry 146, 194–199 (1989).
Hallmayer, J. et al. On the twin risk in autism. Am. J. Hum. Genet. 71, 941–946 (2002).
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).
Risch, N. et al. A genomic screen of autism: evidence for a multilocus etiology. Am. J. Hum. Genet. 65, 493–507 (1999).
Schellenberg, G.D. et al. Evidence for genetic linkage of autism to chromosomes 7 and 4. Mol. Psychiatry 11, 979 (2006).
Freitag, C.M. The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol. Psychiatry 12, 2–22 (2007).
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).
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).
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).
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).
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).
Kong, X. et al. A combined linkage-physical map of the human genome. Am. J. Hum. Genet. 75, 1143–1148 (2004).
Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247 (1995).
Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 445–454 (2006).
Persico, A.M. & Bourgeron, T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 29, 349–358 (2006).
Feng, J. et al. High frequency of neurexin 1β signal peptide structural variants in patients with autism. Neurosci. Lett. 409, 10–13 (2006).
de Vries, B.B. et al. Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet. 77, 606–616 (2005).
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).
Houlden, H. & Reilly, M.M. Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease. Neuromolecular Med. 8, 43–62 (2006).
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).
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).
Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).
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).
Stone, J.L. et al. Evidence for sex-specific risk alleles in autism spectrum disorder. Am. J. Hum. Genet. 75, 1117–1123 (2004).
Falconer, D.S. Introduction to Quantitative Genetics (Longman, London, 1981).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Camp, N.J. & Farnham, J.M. Correcting for multiple analyses in genomewide linkage studies. Ann. Hum. Genet. 65, 577–582 (2001).
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).
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).
Varoqueaux, F. et al. Neuroligins determine synapse maturation and function. Neuron 51, 741–754 (2006).
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).
Shinohe, A. et al. Increased serum levels of glutamate in adult patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 1472–1477 (2006).
Kugler, P. & Schleyer, V. Developmental expression of glutamate transporters and glutamate dehydrogenase in astrocytes of the postnatal rat hippocampus. Hippocampus 14, 975–985 (2004).
Belmonte, M.K. & Bourgeron, T. Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat. Neurosci. 9, 1221–1225 (2006).
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).
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).
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).
Rinaldo, A. et al. Characterization of multilocus linkage disequilibrium. Genet. Epidemiol. 28, 193–206 (2005).
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).
McPeek, M.S., Wu, X. & Ober, C. Best linear unbiased allele-frequency estimation in complex pedigrees. Biometrics 60, 359–367 (2004).
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).
McQueen, M.B., Blacker, D. & Laird, N.M. Variance calculations for identity-by-descent estimation. Am. J. Hum. Genet. 78, 914–921 (2006).
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).
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).
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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.
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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)
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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
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DOI: https://doi.org/10.1038/ng1985
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