Functional impact of global rare copy number variation in autism spectrum disorders

Journal name:
Nature
Volume:
466,
Pages:
368–372
Date published:
DOI:
doi:10.1038/nature09146
Received
Accepted
Published online

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable (~90%)3, the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4×10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

At a glance

Figures

  1. CNV discovery and characterization.
    Figure 1: CNV discovery and characterization.

    Comprehensive procedures were used to identify the rare CNV data set (boxed). Dashed arrows indicate CNVs not included in downstream analyses. Labels af are as follows: a, SNP and intensity quality control (QC) with ancestry estimation; b, QC for CNV calls; c, pilot validation experiments using quantitative PCR were used to evaluate the false discovery rate; d, rare CNVs in samples of European ancestry were defined as≥30kb in size and present in the total sample set at a frequency <1%. A total of 70 out of 996 (17%) of ASD cases were analysed on different lower-resolution arrays in previous studies9, 10, 28. Label e indicates that all CNVs were computationally verified and at least 40% of case CNVs were also experimentally validated by qPCR and/or independent Agilent or other SNP microarrays; f, 3,677 additional European ancestry controls were used to test specific loci from the primary burden analyses. Additional details are in the Methods and Supplementary Information. ID, intellectual disability.

  2. CNV burden in known ASD and/or intellectual disability genes.
    Figure 2: CNV burden in known ASD and/or intellectual disability genes.

    a, Proportion of samples with CNVs overlapping genes and loci known to be associated in ASD with or without intellectual disability (ID) or intellectual disability only, as well as published candidate genes and loci for ASD (Supplementary Table 9). To select for CNVs with maximal impact, they needed to intersect genes and overlap the target loci by≥50% of their length. Fisher’s exact test P-values for significant differences (P0.05, one tailed) are shown. NS, not significant. b, Enrichment analysis for genes overlapped by rare CNVs in cases compared to controls for the three gene sets in a, relative to the whole genome. Odds ratio and 95% confidence intervals are given for each gene set. Empirical P-values for gene-set enrichment are indicated above each odds ratio. All P-values <0.1 are listed.

  3. A functional map of ASD.
    Figure 3: A functional map of ASD.

    Enrichment results were mapped as a network of gene sets (nodes) related by mutual overlap (edges), where the colour (red, blue or yellow) indicates the class of gene set. Node size is proportional to the total number of genes in each set and edge thickness represents the number of overlapping genes between sets. a, Gene sets enriched for deletions are shown (red) with enrichment significance (FDR q-value) represented as a node colour gradient. Groups of functionally related gene sets are circled and labelled (groups, filled green circles; subgroups, dashed line). b, An expanded enrichment map shows the relationship between gene sets enriched in deletions (a) and sets of known ASD/intellectual disability genes. Node colour hue represents the class of gene set (that is, enriched in deletions, red; known disease genes (ASD and/or intellectual disability (ID) genes), blue; enriched only in disease genes, yellow). Edge colour represents the overlap between gene sets enriched in deletions (green), from disease genes to enriched sets (blue), and between sets enriched in deletions and in disease genes or between disease gene-sets only (orange). The major functional groups are highlighted by filled circles (enriched in deletions, green; enriched in ASD/intellectual disability, blue).

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  1. The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.

    • Dalila Pinto,
    • Andrew R. Carson,
    • Guillermo Casallo,
    • Brian H.Y. Chung,
    • Cheryl Cytrynbaum,
    • Jennifer L. Howe,
    • Anath C. Lionel,
    • Xiao-Qing Liu,
    • Christian R. Marshall,
    • Ohsuke Migita,
    • Tara Paton,
    • Aparna Prasad,
    • Jessica Rickaby,
    • Katherine Sansom,
    • Daisuke Sato,
    • Bhooma Thiruvahindrapduram,
    • Zhouzhi Wang,
    • Rosanna Weksberg,
    • Andrew D. Paterson &
    • Stephen W. Scherer
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

    • Alistair T. Pagnamenta,
    • Penny Farrar,
    • Richard Holt,
    • Ghazala K. Mirza,
    • Jiannis Ragoussis,
    • Inês Sousa,
    • Nuala Sykes,
    • Kirsty Wing &
    • Anthony P. Monaco
  3. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

    • Lambertus Klei,
    • Shawn Wood &
    • Bernie Devlin
  4. Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.

    • Richard Anney,
    • Nadia Bolshakova,
    • Sean Brennan,
    • Lynne Cochrane,
    • Elizabeth A. Heron,
    • Matthew Hill,
    • Gillian Hughes,
    • Jane McGrath,
    • Alison Merikangas,
    • Ricardo Segurado,
    • Katherine Tansey,
    • Louise Gallagher &
    • Michael Gill
  5. Banting and Best Department of Medical Research, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.

    • Daniele Merico &
    • Gary D. Bader
  6. School of Medicine and Medical Science University College, Dublin 4, Ireland.

    • Regina Regan,
    • Judith Conroy,
    • Jillian Casey,
    • Andrew Green,
    • Naisha Shah &
    • Sean Ennis
  7. Instituto Nacional de Saude Dr Ricardo Jorge 1649-016 Lisbon and Instituto Gulbenkian de Cîencia, 2780-156 Oeiras, Portugal.

    • Tiago R. Magalhaes,
    • Catarina Correia,
    • Ana F. Sequeira &
    • Astrid M. Vicente
  8. BioFIG—Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, C2.2.12, Campo Grande, 1749-016 Lisboa, Portugal.

    • Tiago R. Magalhaes,
    • Catarina Correia,
    • Ana F. Sequeira &
    • Astrid M. Vicente
  9. Program in Neurogenetics, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.

    • Brett S. Abrahams &
    • Daniel H. Geschwind
  10. Hospital Pediátrico de Coimbra, 3000 – 076 Coimbra, Portugal.

    • Joana Almeida,
    • Frederico Duque &
    • Guiomar Oliveira
  11. Department of Biology, University of Bologna, 40126 Bologna, Italy.

    • Elena Bacchelli &
    • Elena Maestrini
  12. Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK.

    • Anthony J. Bailey,
    • Magdalena Laskawiec,
    • Katy Renshaw &
    • Simon Wallace
  13. Newcomen Centre, Guy’s Hospital, London SE1 9RT, UK.

    • Gillian Baird
  14. Stella Maris Institute for Child and Adolescent Neuropsychiatry, 56128 Calambrone (Pisa), Italy.

    • Agatino Battaglia,
    • Roberta Igliozzi,
    • Barbara Parrini &
    • Raffaella Tancredi
  15. Child and Adolescent Mental Health, University of Newcastle, Sir James Spence Institute, Newcastle upon Tyne NE1 4LP, UK.

    • Tom Berney,
    • Ann Le Couteur &
    • Helen McConachie
  16. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University Frankfurt, 60528 Frankfurt, Germany.

    • Sven Bölte,
    • Eftichia Duketis,
    • Christine M. Freitag &
    • Fritz Poustka
  17. Department of Child and Adolescent Psychiatry, Institute of Psychiatry, London SE5 8AF, UK.

    • Patrick F. Bolton
  18. Human Genetics and Cognitive Functions, Institut Pasteur; University Paris Diderot-Paris 7, CNRS URA 2182, Fondation FondaMental, 75015 Paris, France.

    • Thomas Bourgeron
  19. Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehab, University of Toronto, Toronto, Ontario M5G 1X8, Canada.

    • Jessica Brian,
    • Irene Drmic,
    • Carolyn Noakes,
    • Wendy Roberts &
    • Lili Senman
  20. Department of Pediatrics and Psychology, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada.

    • Susan E. Bryson
  21. Autism and Communicative Disorders Centre, University of Michigan, Ann Arbor, Michigan 48109-2054, USA.

    • Christina Corsello,
    • Vanessa Hus &
    • Catherine Lord
  22. Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center, and Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, USA.

    • Emily L. Crawford,
    • Sabata C. Lund,
    • Susanne Thomson,
    • Brian L. Yaspan &
    • James S. Sutcliffe
  23. Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.

    • Andrew Crossett,
    • Kathryn Roeder &
    • Jing Wu
  24. Autism Speaks, New York 10016, USA.

    • Geraldine Dawson
  25. Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-3366, USA.

    • Geraldine Dawson
  26. Department of Child Psychiatry, University Medical Center, Utrecht 3508 GA, The Netherlands.

    • Maretha de Jonge &
    • Herman Van Engeland
  27. INSERM U 955, Fondation FondaMental, APHP, Hôpital Robert Debré, Child and Adolescent Psychiatry, 75019 Paris, France.

    • Richard Delorme
  28. Department of Speech and Hearing Sciences, University of Washington, Seattle, Washington 98195, USA.

    • Annette Estes
  29. Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John’s Newfoundland A1B 3V6, Canada.

    • Bridget A. Fernandez
  30. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida 33101, USA.

    • Susan E. Folstein,
    • John Gilbert,
    • Michael L. Cuccaro &
    • Margaret A. Pericak-Vance
  31. Division of Psychiatry, McGill University, Montreal, Quebec H3A 1A1, Canada.

    • Eric Fombonne
  32. Department of Child and Adolescent Psychiatry, Göteborg University, Göteborg S41345, Sweden.

    • Christopher Gillberg &
    • Gudrun Nygren
  33. The Center for Applied Genomics, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

    • Joseph T. Glessner,
    • Hakon Hakonarson,
    • Cecilia Kim &
    • Kai Wang
  34. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

    • Jeremy Goldberg,
    • Christina Strawbridge,
    • Ann P. Thompson &
    • Peter Szatmari
  35. Academic Department of Child Psychiatry, Booth Hall of Children’s Hospital, Blackley, Manchester M9 7AA, UK.

    • Jonathan Green
  36. Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612, USA.

    • Stephen J. Guter,
    • Jeff Salt &
    • Edwin H. Cook
  37. Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    • Hakon Hakonarson
  38. Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

    • Sabine M. Klauck &
    • Annemarie Poustka
  39. The Seaver Autism Center for Research and Treatment, Department of Psychiatry, Mount Sinai School of Medicine, New York 10029, USA.

    • Alexander Kolevzon,
    • Latha Soorya,
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    • Danielle Zurawiecki &
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  40. Department of Medicine, University of Washington, Seattle, Washington 98195, USA.

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  41. Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, California 90036-4234, USA.

    • Vlad Kustanovich &
    • Clara M. Lajonchere
  42. Centre for Integrated Genomic Medical Research, University of Manchester, Manchester M13 9PT, UK.

    • Janine A. Lamb
  43. INSERM U995, Department of Psychiatry, Groupe Hospitalier Henri Mondor-Albert Chenevier, AP-HP; University Paris 12, Fondation FondaMental, Créteil 94000, France.

    • Marion Leboyer
  44. Nathan Kline Institute for Psychiatric Research (NKI), 140 Old Orangeburg Road, Orangeburg, New York 10962, USA.

    • Bennett L. Leventhal
  45. Department of Child and Adolescent Psychiatry, New York University and NYU Child Study Center, 550 First Avenue, New York, New York 10016, USA.

    • Bennett L. Leventhal
  46. Department of Psychiatry, Division of Child and Adolescent Psychiatry and Child Development, Stanford University School of Medicine, Stanford, California 94304, USA.

    • Linda Lotspeich &
    • Joachim Hallmayer
  47. Department of Pediatrics, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

    • William Mahoney
  48. Centre d’Eudes et de Recherches en Psychopathologie, University de Toulouse Le Mirail, Toulouse 31200, France.

    • Carine Mantoulan,
    • Bernadette Roge &
    • Kerstin Wittemeyer
  49. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

    • Christopher J. McDougle,
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  50. Psychiatry Department, University of Utah Medical School, Salt Lake City, Utah 84108, USA.

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  51. Departments of Psychiatry and Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

    • Nancy J. Minshew
  52. Department of Psychiatry and Behavioural Sciences, University of Washington, Seattle, Washington 98195, USA.

    • Jeff Munson
  53. Department of Human Genetics, University of California—Los Angeles School of Medicine, Los Angeles, California 90095, USA.

    • Stanley F. Nelson &
    • Rita M. Cantor
  54. Centre for Addiction and Mental Health, Clarke Institute and Department of Psychiatry, University of Toronto, Toronto, Ontario M5G 1X8, Canada.

    • Abdul Noor &
    • John B. Vincent
  55. University Department of Child Psychiatry, Athens University, Medical School, Agia Sophia Children’s Hospital, 115 27Athens, Greece.

    • Katerina Papanikolaou &
    • John Tsiantis
  56. Insitutes of Neuroscience and Health and Society, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK.

    • Tom Berney,
    • Ann Le Couteur,
    • Helen McConachie &
    • Jeremy R. Parr
  57. Department of Medicine, School of Epidemiology and Health Science, University of Manchester, Manchester M13 9PT, UK.

    • Andrew Pickles
  58. INSERM U952 and CNRS UMR 7224 and UPMC Univ Paris 06, Paris 75005, France.

    • Marion Pilorge &
    • Catalina Betancur
  59. Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, North Carolina 27599-3366, USA.

    • Joseph Piven
  60. MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

    • Chris P. Ponting &
    • Caleb Webber
  61. Social, Genetic and Developmental Psychiatry Centre, Institute Of Psychiatry, London SE5 8AF, UK.

    • Michael L. Rutter
  62. Department of Psychiatry, Washington University in St Louis, School of Medicine, St Louis, Missouri 63130, USA.

    • Laura J. Bierut &
    • John P. Rice
  63. Department of Pediatrics and Howard Hughes Medical Institute Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

    • Val C. Sheffield
  64. Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children’s Hospital and The Ohio State University, Columbus, Ohio 43205, USA.

    • Olaf Stein &
    • Veronica J. Vieland
  65. Neuropsichiatria Infantile, Ospedale Santa Croce, 61032 Fano, Italy.

    • Vera Stoppioni
  66. Child Study Centre, Yale University, New Haven, Connecticut 06520, USA.

    • Fred Volkmar
  67. Department of Psychiatry, Carver College of Medicine, Iowa City, Iowa 52242, USA.

    • Thomas H. Wassink
  68. Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2J3, Canada.

    • Lonnie Zwaigenbaum
  69. Center for Human Genetics Research, Vanderbilt University Medical Centre, Nashville, Tennessee 37232, USA.

    • Jonathan L. Haines
  70. Pathology and Laboratory Medicine, University of Pennsylvania, Pennsylvania 19104, USA.

    • Gerard D. Schellenberg
  71. Departments of Biostatistics and Medicine, University of Washington, Seattle, Washington 98195, USA.

    • Ellen M. Wijsman
  72. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A1, Canada.

    • Gary D. Bader &
    • Stephen W. Scherer
  73. Deceased.

    • Annemarie Poustka

Contributions

D.P., J.D.B., R.M.C., E.H.C., H.C., M.C., B.D., S.E., L.G., D.H.G., M.G., J.L.H., J.H., J.M., A.P.M., J.I.N., A.D.P., M.A.P.-V., G.D.S., P.S., A.M.V., V.J.V., E.M.W., J.S.S., C.B. and S.W.S. were leading contributors in the design, analysis and writing of this study. A.J.B., A.B., G.D., C.M.F., H.H., S.M.K., E.M., S.F.N., G.O., J.P., T.H.W., J.D.B., R.M.C., E.H.C., H.C., B.D., S.E., L.G., D.H.G., M.G., J.L.H., J.H., A.P.M., J.I.N., A.D.P., M.A.P.-V., G.D.S., P.S., A.M.V., V.J.V., E.M.W., S.W.S., J.S.S. and C.B. are Lead Autism Genome Project Consortium (AGP) investigators who contributed equally to this project. All other authors were either involved in phenotype and clinical assessments or have participated in experiments and analysis.

Competing financial interests

L.J. Bierut and J.P. Rice are inventors on the patent “Markers for Addiction” (US 20070258898) covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction. L.J. Bierut served as a consultant for Pfizer Inc. in 2008.

Corresponding author

Correspondence to:

Author details

Supplementary information

PDF files

  1. Supplementary Information (3.8M)

    This file contains Supplementary Information comprising: Autism spectrum disorder (ASD) sample and control collections; Genotyping and data cleaning; CNV detection and quality control evaluation; CNV verification; Rare CNV burden analysis; Gene-set enrichment and functional map; Supplementary Figures 1-12 with legends, Supplementary Tables 1-13 (see separate files for tables 8 and 13), Acknowledgements and References.

Excel files

  1. Supplementary Table 8 (699K)

    This table contains rare CNVs in 996 ASD cases.

  2. Supplementary Table 13 (94K)

    This table contains a list of gene-sets enriched for deletions.

Comments

  1. Report this comment #11148

    Peter Melzer said:

    This study identifies genes with rare copy number variants that may play a role in autism spectrum disorder (ASD). The genes were identified by probabilistic association, comparing the genetic sequences of people with ASD to those of people without ASD. How the products of these genes may affect brain development in ASD remains to be established.

    As in previous genome-wide sequencing studies, the number of genes identified in this study is large. The products of some genes with known functions seem involved in fundamental processes of nerve cell development and the formation of nerve cell connections. This is an important, though not entirely unexpected finding. Further investigation of the precise role of these molecules will hopefully help uncover the origin of ASD.

    However, the genes implicated in this study should impact nerve cells everywhere in the brain. It is difficult to conceive, how their modification should mainly affect brain structures known to play a role in ASD, e.g. the parietal lobe of the cerebral cortex.

    Moreover, the endeavor to tease apart the molecular mechanisms that may underly subtypes of ASD appears daunting. Unraveling causation in ASD seems particularly complicated by the fact that the disorder is the result of complex interactions early in brain development among numerous causes with a great diversity of origin.

    The greatest potential of elucidating cause and effect may lie with cases in which inherited deletions are associated with ASD.

    Read more here:
    http://brainmindinst.blogspot.com/2008/07/autism-genes-revisited.html

  2. Report this comment #11154

    David A. said:

    I just wanted to say thanks for this great research, we really appreciate this work being done around authism. Thanks to Nature too for publishing it.

    I hope we can disover all authism related genes so that some kind of medical treatment can be created soon, and it can benefit the people we love that have some kind of ASD, and their children too.

    You really give hope to many people with this work. Please keep it up.

  3. Report this comment #11160

    Robin P Clarke said:

    The main importance of this study arguably lies in what it has not found. It has involved a huge amount of time and effort expended on seeking for pathological genetics underlying this so-called 'disease' or 'disorder' (ASD), and yet such pathology as it has found can account for only a few percent of all the autism-related cases under study. That doesn't surprise me at all. It is entirely in accordance with my "still-unchallenged theory published in Person Ind Diff in 1993":http://www.autismcauses.info. . Therein, I agreed with those who reckoned that autism was a polygenetic condition just as IQ variance was polygenetic. The vast majority of genetic variations associated with autism would be the very same "normal", non-pathological, variations that cause IQ variance — for the reasons my theory explained.

    The authors here are scraping the bottom of the wrong barrel, looking for the wrong things, and as a result they find the wrong things that then lead them away from the main story of autism causation. So-called ASD is a very rough and broad empirical diagnosis which is liable to include quite a number of cases who do not really belong in the true autism broad syndrome but just have some genetic twirks that make them behave rather similarly (like a bee misleadingly resembles a wasp). This study could have had more hope if it had used narrowly-defined core autism as its cases.

    But the people here are working to a pre-set agenda, within what we might call the disease model. This presumes that something has "gone wrong" with these individuals and seeks out that "wrong". Furthermore they assume it is genetic! It may be significant that the 90% genetic stat is supported only by a reference that is 15 years old. In my 1993-published theory I indicated conditions in which autism would change from being mainly genetic to being mainly environmental. And exactly that has now happened in.the last 2 decades.

    The pre-set agenda here is to find what has "gone wrong" and then find a drug to "put it right" and voila! big profits for corporate science (they hope).

    It is sad to see such huge publicity given to such marginal fringe findings, while the real central ressearch is all but completely hidden by this hype. For instance the Autism Research Institute's evidence that DMSA chelation to remove mercury can cure about 70% of cases, as documented by online videos of the cured children. But that doesn't generate profits for the corporations, or jobs for the researchers listed here. So it's ignored, despised and even persecuted just as was Semmelweiss's immense discovery, inter many alias. Or they could have just spent a little time more enlighteningly reading my 1993 paper. But then Wegener's continental drift had to wait through 50 years of professional derision so perhaps I'm calling time a little prematurely here. Overwhelming evidence (reviewed in my forthcoming update) proves that the main cause of autism (ASDs etc) nowadays is the non-gamma-2 dental amalgams introduced.in the 1970s. www.autismcauses.info

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