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A genome-wide linkage and association scan reveals novel loci for autism

Abstract

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success1. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

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Figure 1: Genome-wide linkage results.
Figure 2: SEMA5A expression in autism brains.

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References

  1. Abrahams, B. S. & Geschwind, D. H. Advances in autism genetics: on the threshold of a new neurobiology. Nature Rev. Genet. 9, 341–355 (2008)

    Article  CAS  Google Scholar 

  2. Weiss, L. A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008)

    Article  CAS  Google Scholar 

  3. Geschwind, D. H. et al. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am. J. Hum. Genet. 69, 463–466 (2001)

    Article  CAS  Google Scholar 

  4. Abecasis, G. R. & Wigginton, J. E. Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am. J. Hum. Genet. 77, 754–767 (2005)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Sklar, P. et al. Whole-genome association study of bipolar disorder. Mol. Psychiatry 13, 558–569 (2008)

    Article  CAS  Google Scholar 

  7. Melin, M. et al. Constitutional downregulation of SEMA5A expression in autism. Neuropsychobiology 54, 64–69 (2006)

    Article  CAS  Google Scholar 

  8. Gaffrey, M. S. et al. Atypical participation of visual cortex during word processing in autism: an fMRI study of semantic decision. Neuropsychologia 45, 1672–1684 (2007)

    Article  Google Scholar 

  9. Hirota, H. et al. Williams syndrome deficits in visual spatial processing linked to GTF2IRD1 and GTF2I on chromosome 7q11.23. Genet. Med. 5, 311–321 (2003)

    Article  CAS  Google Scholar 

  10. Edelmann, L. et al. An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism. J. Med. Genet. 44, 136–143 (2007)

    Article  CAS  Google Scholar 

  11. van Hagen, J. M. et al. Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome. Neurobiol. Dis. 26, 112–124 (2007)

    Article  CAS  Google Scholar 

  12. Wang, K. et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459, 528–533 (2009)

    Article  ADS  CAS  Google Scholar 

  13. Zafeiriou, D. I., Ververi, A. & Vargiami, E. Childhood autism and associated comorbidities. Brain Dev. 29, 257–272 (2007)

    Article  Google Scholar 

  14. Szatmari, P. et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genet. 39, 319–328 (2007)

    Article  CAS  Google Scholar 

  15. Bhangale, T. R., Rieder, M. J. & Nickerson, D. A. Estimating coverage and power for genetic association studies using near-complete variation data. Nature Genet. 40, 841–843 (2008)

    Article  CAS  Google Scholar 

  16. Risch, N. J. Searching for genetic determinants in the new millennium. Nature 405, 847–856 (2000)

    Article  CAS  Google Scholar 

  17. Arking, D. E. et al. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 82, 160–164 (2008)

    Article  CAS  Google Scholar 

  18. Alarcón, M. et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet. 82, 150–159 (2008)

    Article  Google Scholar 

  19. Bakkaloglu, B. et al. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am. J. Hum. Genet. 82, 165–173 (2008)

    Article  CAS  Google Scholar 

  20. Campbell, D. B. et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann. Neurol. 62, 243–250 (2007)

    Article  Google Scholar 

  21. Campbell, D. B. et al. A genetic variant that disrupts MET transcription is associated with autism. Proc. Natl Acad. Sci. USA 103, 16834–16839 (2006)

    Article  ADS  CAS  Google Scholar 

  22. Di Rienzo, A. Population genetics models of common diseases. Curr. Opin. Genet. Dev. 16, 630–636 (2006)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007)

    Article  CAS  Google Scholar 

  25. Lord, C., Rutter, M. & Le Couteur, A. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J. Autism Dev. Disord. 24, 659–685 (1994)

    Article  CAS  Google Scholar 

  26. Korn, J. M. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nature Genet. 40, 1253–1260 (2008)

    Article  CAS  Google Scholar 

  27. McCarroll, S. A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genet. 40, 1166–1174 (2008)

    Article  CAS  Google Scholar 

  28. Hirschhorn, J. N. & Daly, M. J. Genome-wide association studies for common diseases and complex traits. Nature Rev. Genet. 6, 95–108 (2005)

    Article  CAS  Google Scholar 

  29. Mitchell, A. A., Cutler, D. J. & Chakravarti, A. Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test. Am. J. Hum. Genet. 72, 598–610 (2003)

    Article  CAS  Google Scholar 

  30. The Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007)

    Article  Google Scholar 

  31. Gauthier, J. et al. Autism spectrum disorders associated with X chromosome markers in French-Canadian males. Mol. Psychiatry 11, 206–213 (2006)

    Article  CAS  Google Scholar 

  32. Lord, C. et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J. Autism Dev. Disord. 30, 205–223 (2000)

    Article  CAS  Google Scholar 

  33. Berument, S. K., Rutter, M., Lord, C., Pickles, A. & Bailey, A. Autism screening questionnaire: diagnostic validity. Br. J. Psychiatry 175, 444–451 (1999)

    Article  CAS  Google Scholar 

  34. Le Couteur, A. et al. Autism Diagnostic Interview: A standardized investigator-based instrument. J. Autism Dev. Disord. 19, 363–387 (1989)

    Article  CAS  Google Scholar 

  35. Tyrer, P. J. Personality Disorders: Diagnosis, Management, and Course (Wright, 1988)

    Google Scholar 

  36. Landa, R. et al. Social language use in parents of autistic individuals. Psychol. Med. 22, 245–254 (1992)

    Article  CAS  Google Scholar 

  37. Mattila, M. L. et al. An epidemiological and diagnostic study of Asperger syndrome according to four sets of diagnostic criteria. J. Am. Acad. Child Adolesc. Psychiatry 46, 636–646 (2007)

    Article  Google Scholar 

  38. Wechsler, D. Wechsler Intelligence Scale for Children Third edn (The Psychological Corporation, 1991)

    Google Scholar 

  39. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic Criteria for Research (WHO, 1993)

  40. Auranen, M. et al. A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25-27. Am. J. Hum. Genet. 71, 777–790 (2002)

    Article  Google Scholar 

  41. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) 4 edn (APA, 1994)

  42. Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008)

    Article  CAS  Google Scholar 

  43. Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔC T method. Methods 25, 402–408 (2001)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all of the families who have participated in and contributed to the public resources that we have used in these studies. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The Gene Discovery Project of Johns Hopkins was funded by grants from the National Institutes of Mental Health (MH60007, MH081754) and the Simons Foundation. This study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. Support for the Homozygosity Mapping Collaborative for Autism (HMCA) came from NIMH (1R01 MH083565), the Nancy Lurie Marks (NLM) Family Foundation and the Simons Foundation. Eric M. Morrow is supported by the NIMH (1K23MH080954). Support for the Iranian family sample was provided by the Special Education Organization of Iran, under the Iranian Ministry of Education. Lauren A. Weiss was supported by a Ruth L. Kirschstein National Research Service Award and is currently supported by the International Mental Health Research Organization. The collection of data and biomaterials that participated in the National Institute of Mental Health (NIMH) Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219 and MH00980; National Health Medical Research Council grant 0034328; and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), and the endowment fund of the Nancy Pritzker Laboratory (Stanford); and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The NIMH collection Principal Investigators and Co-Investigators were: Neil Risch, Richard M. Myers, Donna Spiker, Linda J. Lotspeich, Joachim F. Hallmayer, Helena C. Kraemer, Roland D. Ciaranello, Luigi Luca Cavalli-Sforza (Stanford University, Stanford); William M. McMahon and P. Brent Petersen (University of Utah, Salt Lake City). The Stanford team is indebted to the parent groups and clinician colleagues who referred families and extends their gratitude to the families with individuals with autism who were partners in this research. The collection data and biomaterials also come from the Autism Genetic Resource Exchange (AGRE) collection. This program has been supported by a National Institute of Health grant MH64547 and the Cure Autism Now Foundation. The AGRE collection Principal Investigator is Daniel H. Geschwind (UCLA). The Co-Principal Investigators include Stanley F. Nelson and Rita M. Cantor (UCLA), Christa Lese Martin (Univ. Chicago), T. Conrad Gilliam (Columbia). Co-Investigators include Maricela Alarcon (UCLA), Kenneth Lange (UCLA), Sarah J. Spence (UCLA), David H. Ledbetter (Emory) and Hank Juo (Columbia). Scientific oversight of the AGRE program is provided by a steering committee (Chair: Daniel H. Geschwind; Members: W. Ted Brown, Maja Bucan, Joseph D. Buxbaum, T. Conrad Gilliam, David Greenberg, David H. Ledbetter, Bruce Miller, Stanley F. Nelson, Jonathan Pevsner, Carol Sprouse, Gerard D. Schellenberg and Rudolph Tanzi). The Autism Genome Project (AGP) work was supported by the following grants: (1) The Hilibrand Foundation (Principal Investigator Joachim F. Hallmayer); (2) Autism Speaks (for the AGP); (3) grants from the National Institutes of Health (NIH) MH61009 (James S. Sutcliffe), MH55135 (Susan E. Folstein), MH55284 (Joseph Piven), HD055782 (Ellen M. Wijsman), NS042165 (Joachim F. Hallmayer); (4) Fundação para a Ciência e Tecnologia (POCTI/39636/ESP/2001) Fundação Calouste Gulbenkian (Astrid Vincente); (5) INSERM, Fondation de France, Fondation Orange, Fondation pour la Recherche Médicale (Catalina Betancur, Marion Leboyer), and the Swedish Science Council (Christopher Gillberg); (6) The Seaver Foundation (Joseph D. Buxbaum); (7) The Children’s Medical & Research Foundation (CMRF), Our Lady’s Children’s Hospital, Crumlin, Ireland (Sean Ennis); (8) The Medical Research Council (MRC) (Anthony P. Monaco, Anthony J. Bailey). Fresh-frozen brain tissue samples were obtained through the Autism Tissue Program and the Harvard Brain Bank.

Author Contributions L.A.W., D.E.A., M.J.D. and A. Chakravarti led design and execution of joint scan analyses and manuscript writing. Johns Hopkins University–NIMH genome scan team: D.E.A. and A. Chakravarti led study design and analysis of scan; C.W.B. and E.H.C. provided evaluation of phenotype data, phenotype definition from primary data and editing of the manuscript; K. West, A.O’C. and G.H. conducted primary and replication genotyping with allele calling; R.L.T. and A.B.W. performed expression analysis and editing of the manuscript. Autism Consortium–AGRE genome scan team: L.A.W., T.G. and M.J.D. performed data processing and analysis for the genome-wide association scan; S-C.C., E.M.H., E.M.M., R.S. and S.L.S. provided evaluation of phenotype data and phenotype definition from primary data; S.G., C. Gates, C. Sougnez and C. Stevens led the genotyping team; A.K., J.K., F.K., S.M., B.N. and S.P. performed and evaluated allele calling and advised the analysis; M.J.D., L.A.W., R.T., P.S., S.L.S., J. Gusella and D.A. designed and initiated the study and provided manuscript comments and edits. Replication teams: each replication team provided genotypes, phenotypes and analysis of top ranking SNPs from the combined genome-wide association scan and contributed comments during manuscript preparation.

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Correspondence to Mark J. Daly, Aravinda Chakravarti, Aravinda Chakravarti or Mark J. Daly.

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[Competing Interests: Aravinda Chakravarti is a paid member of the Scientific Advisory Board of Affymetrix, a role that is managed by the Committee on Conflict of Interest of the Johns Hopkins University School of Medicine.]

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Weiss, L., Arking, D. & The Gene Discovery Project of Johns Hopkins & the Autism Consortium. A genome-wide linkage and association scan reveals novel loci for autism. Nature 461, 802–808 (2009). https://doi.org/10.1038/nature08490

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