, Volume 231, Issue 6, pp 1201–1216 | Cite as

Biomarkers in autism spectrum disorder: the old and the new

  • Barbara Ruggeri
  • Ugis Sarkans
  • Gunter Schumann
  • Antonio M. PersicoEmail author



Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder with onset during early childhood and typically a life-long course. The majority of ASD cases stems from complex, ‘multiple-hit’, oligogenic/polygenic underpinnings involving several loci and possibly gene–environment interactions. These multiple layers of complexity spur interest into the identification of biomarkers able to define biologically homogeneous subgroups, predict autism risk prior to the onset of behavioural abnormalities, aid early diagnoses, predict the developmental trajectory of ASD children, predict response to treatment and identify children at risk for severe adverse reactions to psychoactive drugs.


The present paper reviews (a) similarities and differences between the concepts of ‘biomarker’ and ‘endophenotype’, (b) established biomarkers and endophenotypes in autism research (biochemical, morphological, hormonal, immunological, neurophysiological and neuroanatomical, neuropsychological, behavioural), (c) -omics approaches towards the discovery of novel biomarker panels for ASD, (d) bioresource infrastructures and (e) data management for biomarker research in autism.


Known biomarkers, such as abnormal blood levels of serotonin, oxytocin, melatonin, immune cytokines and lymphocyte subtypes, multiple neuropsychological, electrophysiological and brain imaging parameters, will eventually merge with novel biomarkers identified using unbiased genomic, epigenomic, transcriptomic, proteomic and metabolomic methods, to generate multimarker panels. Bioresource infrastructures, data management and data analysis using artificial intelligence networks will be instrumental in supporting efforts to identify these biomarker panels.


Biomarker research has great heuristic potential in targeting autism diagnosis and treatment.


Autism Biobank Biomarker Endophenotype Macrocephaly Melatonin Metabolomics Oxytocin Serotonin 



This work was supported by the Italian Ministry for University, Scientific Research and Technology (PRIN no. 2006058195 and no. 2008BACT54_002), the Italian Ministry of Health (RFPS-2007-5-640174 and RF-2011-02350537), the Fondazione Gaetano e Mafalda Luce (Milan, Italy), Autism Aid ONLUS (Naples, Italy), Autism Speaks (Princeton, NJ), the Autism Research Institute (San Diego, CA), the European Molecular Biology Laboratory (EMBL), and the Innovative Medicines Initiative Joint Undertaking (EU-AIMS, no. 115300).

Conflict of interest

None declared.


  1. Adolphs R, Spezio ML, Parlier M et al (2008) Distinct face-processing strategies in parents of autistic children. Curr Biol 18:1090–1093PubMedCentralPubMedGoogle Scholar
  2. Alarcón M, Abrahamas BS, Stone JL et al (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82:150–159PubMedCentralPubMedGoogle Scholar
  3. Altelaar AF, Munoz J, Heck AJ (2013) Next-generation proteomics: towards an integrative view of proteome dynamics. Nat Rev Genet 14:35–48PubMedGoogle Scholar
  4. Altieri L, Neri C, Sacco R et al (2011) Urinary p-cresol is elevated in small children with severe autism spectrum disorder. Biomarkers 16:252–260PubMedGoogle Scholar
  5. Anagnostou E, Soorya L, Chaplin W et al (2012) Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 3:16PubMedCentralPubMedGoogle Scholar
  6. Anderson GM, Horne WC, Chatterjee D et al (1990) The hyperserotoninemia of autism. Ann NY Acad Sci 600:331–340PubMedGoogle Scholar
  7. Anney RJ, Kenny EM, O’Dushlaine C et al (2011) Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders. Eur J Hum Genet 19:1082–1089PubMedGoogle Scholar
  8. Ashwood P, Wills S, Van de Water J (2006) The immune response in autism: a new frontier for autism research. J Leukoc Biol 80:1–15PubMedGoogle Scholar
  9. Bailey A, Le Couteur A, Gottesman I et al (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63–77PubMedGoogle Scholar
  10. Bakeman R, Adamson LB (1984) Coordinating attention to people and objects in mother–infant and peer–infant interaction. Child Dev 55:1278–1289PubMedGoogle Scholar
  11. Ball CA, Sherlock G, Parkinson H et al (2002) Standards for microarray data [1]. Science 298:539PubMedGoogle Scholar
  12. Baron-Cohen S (1995) Mindblindness: an essay on autism and theory of mind. Bradford/MIT, CambridgeGoogle Scholar
  13. Baron-Cohen S, Scott FJ, Allison C et al (2009) Prevalence of autism-spectrum conditions: UK school-based population study. Br J Psychiatry 194:500–509PubMedGoogle Scholar
  14. Belmonte MK, Gomot M, Baron-Cohen S (2010) Visual attention in autism families: “unaffected” sibs share atypical frontal activation. J Child Psychol Psychiatry 51:259–276PubMedGoogle Scholar
  15. Ben-David E, Shifman S (2012) Networks of neuronal genes affected by common and rare variants in autism spectrum disorders. PLoS Genet 8(3):e1002556PubMedCentralPubMedGoogle Scholar
  16. Blair RJ (2005) Responding to the emotions of others: dissociating forms of empathy through the study of typical and psychiatric populations. Conscious Cogn 14:698–718PubMedGoogle Scholar
  17. Bradford Y, Haines J, Hutcheson H et al (2001) Incorporating language phenotypes strengthens evidence of linkage to autism. Am J Med Genet 105:539–547PubMedGoogle Scholar
  18. Bradley BP (2012) Finding biomarkers is getting easier. Ecotoxicology 21:631–636PubMedGoogle Scholar
  19. Brazma A, Hingamp P, Quackenbush J et al (2001) Minimum information about a microarray experiment (MIAME)—toward standards for microarray data. Nat Genet 29:365–371PubMedGoogle Scholar
  20. Brazma A, Krestyaninova M, Sarkans U (2006) Standards for systems biology. Nat Rev Genet 7:593–605PubMedGoogle Scholar
  21. Briskman J, Happé F, Frith U (2001) Exploring the cognitive phenotype of autism: weak “central coherence” in parents and siblings of children with autism: II. Real-life skills and preferences. J Child Psychol Psychiatry 42:309–316PubMedGoogle Scholar
  22. Buscema M, Penco S, Grossi E (2012) A novel mathematical approach to define the genes/SNPs conferring risk or protection in sporadic amyotrophic lateral sclerosis based on auto contractive map neural networks and graph theory. Neurol Res Int. doi: 10.1155/2012/478560
  23. Carayol J, Schellenberg GD, Dombroski B et al (2011) Autism risk assessment in siblings of affected children using sex-specific genetic scores. Mol Autism 2:17PubMedCentralPubMedGoogle Scholar
  24. Cass H, Gringras P, March J et al (2008) Absence of urinary opioid peptides in children with autism. Arch Dis Child 93:745–750PubMedGoogle Scholar
  25. Chawarska K, Campbell D, Chen L et al (2011) Early generalized overgrowth in boys with autism. Arch Gen Psychiatry 68:1021–1031PubMedGoogle Scholar
  26. Cook EH Jr, Leventhal BL, Freedman DX (1988) Free serotonin in plasma: autistic children and their first-degree relatives. Biol Psychiatry 24:488–491PubMedGoogle Scholar
  27. Corbett BA, Constantine LJ, Hendren R et al (2009) Examining executive functioning in children with autism spectrum disorder, attention deficit hyperactivity disorder and typical development. Psychiatry Res 166:210–222PubMedCentralPubMedGoogle Scholar
  28. Courchesne E, Pierce K, Schumann CM et al (2007) Mapping early brain development in autism. Neuron 56:399–413PubMedGoogle Scholar
  29. Crino PB (2011) mTOR: a pathogenic signaling pathway in developmental brain malformations. Trends Mol Med 17:734–742PubMedGoogle Scholar
  30. Croen LA, Braunschweig D, Haapanen L et al (2008) Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study. Biol Psychiatry 64:583–588PubMedCentralPubMedGoogle Scholar
  31. Dalton KM, Nacewicz BM, Johnstone T et al (2005) Gaze fixation and the neural circuitry of face processing in autism. Nat Neurosci 8:519–526PubMedGoogle Scholar
  32. Dapretto M, Davies MS, Pfeifer JH et al (2006) Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders. Nat Neurosci 9:28–30PubMedCentralPubMedGoogle Scholar
  33. Dawson G (2008) Early behavioral intervention, brain plasticity, and the prevention of autism spectrum disorder. Dev Psychopathol 20:775–803PubMedGoogle Scholar
  34. Delorme R, Goussé V, Roy I et al (2007) Shared executive dysfunctions in unaffected relatives of patients with autism and obsessive–compulsive disorder. Eur Psychiatry 22:32–38PubMedCentralPubMedGoogle Scholar
  35. De Smaele E, Ferretti E, Gulino A (2010) MicroRNAs as biomarkers for CNS cancer and other disorders. Brain Res 1338:100–111PubMedGoogle Scholar
  36. Dettmer K, Hanna D, Whetstone P et al (2007) Autism and urinary exogenous neuropeptides: development of an on-line SPE-HPLC-tandem mass spectrometry method to test the opioid excess theory. Anal Bioanal Chem 388:1643–1651PubMedGoogle Scholar
  37. Deutsch EW, Ball CA, Berman JJ et al (2008) Minimum information specification for in situ hybridization and immunohistochemistry experiments (MISFISHIE). Nat Biotechnol 26:305–312PubMedGoogle Scholar
  38. Dichter GS, Felder JN, Green SR et al (2012) Reward circuitry function in autism spectrum disorders. Social Cogn Affect Neurosci 7:160–172Google Scholar
  39. Dichter GS (2012) Functional magnetic resonance imaging of autism spectrum disorders. Dialogues Clin Neurosci 14:319–351PubMedCentralPubMedGoogle Scholar
  40. Dinstein I, Heeger DJ, Lorenzi L et al (2012) Unreliable evoked responses in autism. Neuron 75:981–991PubMedCentralPubMedGoogle Scholar
  41. Dolin RH, Alschuler L, Boyer S et al (2006) HL7 clinical document architecture, release 2. J Am Med Inform Assoc 13:30–39PubMedCentralPubMedGoogle Scholar
  42. Ecker C, Marquand A, Mourão-Miranda J et al (2010) Describing the brain in autism in five dimensions—magnetic resonance imaging-assisted diagnosis of autism spectrum disorder using a multiparameter classification approach. J Neurosci 30:10612–10623PubMedGoogle Scholar
  43. Ecker C, Suckling J, Deoni SC et al (2012) Brain anatomy and its relationship to behavior in adults with autism spectrum disorder: a multicenter magnetic resonance imaging study. Arch Gen Psychiatry 69:195–209PubMedGoogle Scholar
  44. Ecker C, Spooren W, Murphy DG (2013) Translational approaches to the biology of autism: false dawn or a new era? Mol Psychiatry 18:435–442PubMedCentralPubMedGoogle Scholar
  45. Elliott P, Peakman TC, Biobank UK (2008) The UK Biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine. Int J Epidemiol 37:234–244PubMedGoogle Scholar
  46. Elsabbagh M, Bedford R, Senju A et al (2013) What you see is what you get: contextual modulation of face scanning in typical and atypical development. Soc Cogn Affect Neurosci. doi: 10.1093/scan/nst012
  47. Emond P, Mavel S, Aïdoud N et al (2013) GC-MS-based urine metabolic profiling of autism spectrum disorders. Anal Bioanal Chem 405:5291–5300Google Scholar
  48. Enticott PG, Kennedy HA, Rinehart NJ et al (2013) Interpersonal motor resonance in autism spectrum disorder: evidence against a global “mirror system” deficit. Front Hum Neurosci 7:218PubMedCentralPubMedGoogle Scholar
  49. Feldman R (2012) Oxytocin and social affiliation in humans. Horm Behav 61:380–391PubMedGoogle Scholar
  50. Fischbach GD, Lord C (2010) The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron 68:192–195PubMedGoogle Scholar
  51. Fombonne E (2009) Epidemiology of pervasive developmental disorders. Pediatr Res 65:591–598PubMedGoogle Scholar
  52. Fridsma DB, Evans J, Hastak S et al (2008) The BRIDG Project: a technical report. J Am Med Inform Assoc 15:130–137PubMedCentralPubMedGoogle Scholar
  53. Gabriele S, Sacco R, Persico AM (2013) Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis. Biol Psychiatry (in press)Google Scholar
  54. Gadde S, Aucoin N, Grethe JS et al (2012) XCEDE: an extensible schema for biomedical data. Neuroinformatics 10:19–32PubMedGoogle Scholar
  55. Gallese V, Fadiga L, Fogassi L, Rizzolatti G (1996) Action recognition in the premotor cortex. Brain 119:593–609PubMedGoogle Scholar
  56. Gilman SR, Iossifov I, Levy D et al (2011) Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70:898–907PubMedCentralPubMedGoogle Scholar
  57. Goines P, Haapanen L, Boyce R et al (2011) Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav Immun 25:514–523PubMedCentralPubMedGoogle Scholar
  58. Gomot M, Belmonte MK, Bullmore ET et al (2008) Brain hyper-reactivity to auditory novel targets in children with high-functioning autism. Brain 131:2479–2488PubMedGoogle Scholar
  59. Gomot M, Wicker B (2012) A challenging, unpredictable world for people with autism spectrum disorder. Int J Psychophysiol 83:240–247PubMedGoogle Scholar
  60. Gottesman II, Shields J (1973) Genetic theorizing and schizophrenia. Br J Psychiatry 122:15–30PubMedGoogle Scholar
  61. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–645PubMedGoogle Scholar
  62. Grether JK, Rosen NJ, Smith KS et al (2009) Investigation of shifts in autism reporting in the California Department of Developmental Services. J Autism Dev Disord 39:1412–1419PubMedGoogle Scholar
  63. Grossi E, Buscema M (2007) Introduction to artificial neural networks. Eur J Gastroenterol Hepatol 19:1046–1054PubMedGoogle Scholar
  64. Gustaw-Rothenberg K, Lerner A, Bonda DJ et al (2010) Biomarkers in Alzheimer’s disease: past, present and future. Biomark Med 4:15–26PubMedCentralPubMedGoogle Scholar
  65. Hallmayer J, Cleveland S, Torres A et al (2011) Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68:1095–1102PubMedGoogle Scholar
  66. Hammock E, Veenstra-Vanderweele J, Yan Z et al (2012) Examining autism spectrum disorders by biomarkers: example from the oxytocin and serotonin systems. J Am Acad Child Adolesc Psychiatry 51:712–721PubMedCentralPubMedGoogle Scholar
  67. Hammond P, Forster-Gibson C, Chudley AE et al (2008) Face-brain asymmetry in autism spectrum disorders. Mol Psychiatry 13:614–623PubMedGoogle Scholar
  68. Happé F (1999) Autism: cognitive deficit or cognitive style. Trends Cogn Sci 3:216–222PubMedGoogle Scholar
  69. Happé F, Briskman J, Frith U (2001) Exploring the cognitive phenotype of autism: weak “central coherence” in parents and siblings of children with autism: I. Experimental tests. J Child Psychol Psychiatry 42:299–307PubMedGoogle Scholar
  70. Happé F, Frith U (2006) The weak coherence account: detail-focused cognitive style in autism spectrum disorders. J Autism Dev Disord 36:5–25PubMedGoogle Scholar
  71. Helsens K, Colaert N, Barsnes H et al (2010) ms-lims, a simple yet powerful open source laboratory information management system for MS-driven proteomics. Proteomics 10:1261–1264PubMedGoogle Scholar
  72. Hermjakob H, Montecchi-Palazzi L, Bader G et al (2004) The HUPO PSI’s molecular interaction format—a community standard for the representation of protein interaction data. Nat Biotechnol 22:177–183PubMedGoogle Scholar
  73. Hertz-Picciotto I, Delwiche L (2009) The rise in autism and the role of age at diagnosis. Epidemiology 20:84–90PubMedGoogle Scholar
  74. Hollander E, Phillips A, King BH et al (2004) Impact of recent findings on study design of future autism clinical trials. CNS Spectr 9:49–56PubMedGoogle Scholar
  75. Hunter LC, O’Hare A, Herron WJ et al (2003) Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol 45:121–128PubMedGoogle Scholar
  76. Jacquemont S, Curie A, des Portes V et al (2011) Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 3:64ra1Google Scholar
  77. Jeste SS, Nelson CA 3rd (2009) Event related potentials in the understanding of autism spectrum disorders: an analytical review. J Autism Dev Disord 39:495–510PubMedGoogle Scholar
  78. John B, Lewis KR (1966) Chromosome variability and geographic distribution in insects. Science 152:711–721PubMedGoogle Scholar
  79. Kaiser MD, Hudac CM, Shultz S et al (2010) Neural signatures of autism. Proc Natl Acad Sci U S A 107:21223–21228PubMedCentralPubMedGoogle Scholar
  80. Kana RK, Keller TA, Minshew NJ, Just MA (2007) Inhibitory control in high functioning autism: decreased activation and underconnectivity in inhibition networks. Biol Psychiatry 62:198–206PubMedGoogle Scholar
  81. Katsui T, Okuda M, Usuda S et al (1986) Kinetics of 3H-serotonin uptake by platelets in infantile autism and developmental language disorder (including five pairs of twins). J Autism Dev Disord 16:69–76PubMedGoogle Scholar
  82. King M, Bearman P (2009) Diagnostic change and the increased prevalence of autism. Intl J Epidemiol 38:1224–1234Google Scholar
  83. Klei L, Sanders SJ, Murtha MT et al (2012) Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism 3:9PubMedCentralPubMedGoogle Scholar
  84. Kleinhans NM, Muller RA, Cohen DN, Courchesne E (2008) Atypical functional lateralization of language in autism spectrum disorders. Brain Res 1221:115–125PubMedCentralPubMedGoogle Scholar
  85. Klin A, Jones W, Schultz R et al (2002) Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism. Arch Gen Psychiat 59:809–816PubMedGoogle Scholar
  86. Klin A, Jones W, Schultz R (2003) The enactive mind—from actions to cognition: lessons from autism. Phil Trans R Soc Land B Biol Sci 358:345–360Google Scholar
  87. Kou Y, Betancur C, Xu H et al (2012) Network- and attribute-based classifiers can prioritize genes and pathways for autism spectrum disorders and intellectual disability. Am J Med Genet C: Semin Med Genet 160C:130–142Google Scholar
  88. Krestyaninova M, Tammisto Y (2012) Services design in a collaborative network for multidisciplinary research projects. IFIP Advances in Information and Communication Technology 380 AICT:273–279Google Scholar
  89. Krestyaninova M, Zarins A, Viksna J et al (2009) A system for information management in BioMedical studies—SIMBioMS. Bioinformatics 25:2768–2769PubMedGoogle Scholar
  90. Krueger F, Kreck B, Franke A, Andrews SR (2012) DNA methylome analysis using short bisulfite sequencing data. Nat Methods 9:145–151PubMedGoogle Scholar
  91. Kumar SL (2013) Examining the characteristics of visuospatial information processing in individuals with high-functioning autism. Yale J Biol Med 86:147–156PubMedCentralPubMedGoogle Scholar
  92. Lajonchere CM, AGRE Consortium (2010) Changing the landscape of autism research: the autism genetic resource exchange. Neuron 68:187–191PubMedCentralPubMedGoogle Scholar
  93. Langille MGI, Eisen JA (2010) Biotorrents: a file sharing service for scientific data. PLoS ONE 5:e10071PubMedCentralPubMedGoogle Scholar
  94. Lee TL, Raygada MJ, Rennert OM (2012) Integrative gene network analysis provides novel regulatory relationships, genetic contributions and susceptible targets in autism spectrum disorders. Gene 496:88–96PubMedCentralPubMedGoogle Scholar
  95. Lesch KP, Wolozin BL, Murphy DL et al (1993) Primary structure of the human platelet serotonin (5-HT) uptake site: identity with the brain 5-HT transporter. J Neurochem 60:2319–2322PubMedGoogle Scholar
  96. Leslie AM, Friedman O, German TP (2004) Core mechanisms in “theory of mind”. Trends Cogn Sci 8:528–533PubMedGoogle Scholar
  97. Lintas C, Sacco R, Persico AM (2012) Genome-wide expression studies in autism spectrum disorder, Rett syndrome, and Down syndrome. Neurobiol Dis 45:57–68PubMedGoogle Scholar
  98. Liu XQ, Paterson AD, Szatmari P et al (2008) Genome-wide linkage analyses of quantitative and categorical autism subphenotypes. Biol Psychiatry 64:561–570PubMedCentralPubMedGoogle Scholar
  99. Lucht MJ, Barnow S, Sonnenfeld C et al (2009) Associations between the oxytocin receptor gene (OXTR) and affect, loneliness and intelligence in normal subjects. Prog Neuropsychopharmacol Biol Psychiatry 33:860–866PubMedGoogle Scholar
  100. Luo R, Sanders SJ, Tian Y et al (2012) Genome-wide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders. Am J Hum Genet 91:38–55PubMedCentralPubMedGoogle Scholar
  101. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307–318PubMedGoogle Scholar
  102. Maguire E, González-Beltrán A, Whetzel PL et al (2013) OntoMaton: a bioportal powered ontology widget for Google Spreadsheets. Bioinformatics 29:525–527PubMedGoogle Scholar
  103. Malesa E, Foss-Feig J, Yoder P, et al (2012) Predicting language and social outcomes at age 5 for later-born siblings of children with autism spectrum disorders. Autism 17:558–570Google Scholar
  104. Malone J, Holloway E, Adamusiak T et al (2010) Modeling sample variables with an experimental factor ontology. Bioinformatics 26:1112–1118PubMedGoogle Scholar
  105. Marazziti D, Muratori F, Cesari A et al (2000) Increased density of the platelet serotonin transporter in autism. Pharmacopsychiatry 33:165–168PubMedGoogle Scholar
  106. Marcus DS, Olsen TR, Ramaratnam M et al (2007) The extensible neuroimaging archive toolkit: an informatics platform for managing, exploring, and sharing neuroimaging data. Neuroinformatics 5:11–33PubMedGoogle Scholar
  107. Mayr M, Zampetaki A, Willeit P et al (2013) MicroRNAs within the continuum of postgenomics biomarker discovery. Arterioscler Thromb Vasc Biol 33:206–214PubMedGoogle Scholar
  108. McBride PA, Anderson GM, Hertzig ME et al (1998) Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry 37:767–776PubMedGoogle Scholar
  109. Melke J, Goubran Botros H, Chaste P et al (2008) Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry 13:90–98PubMedCentralPubMedGoogle Scholar
  110. Mellios N, Sur M (2012) The emerging role of microRNAs in schizophrenia and autism spectrum disorders. Front Psychiatry 3:39PubMedCentralPubMedGoogle Scholar
  111. Mildenberger P, Eichelberg M, Martin E (2002) Introduction to the DICOM standard. Eur Radiol 12:920–927PubMedGoogle Scholar
  112. Miles JH, Hadden LL, Takahashi TN et al (2000) Head circumference is an independent clinical finding associated with autism. Am J Med Genet 95:339–350PubMedGoogle Scholar
  113. Modahl C, Green L, Fein D et al (1998) Plasma oxytocin levels in autistic children. Biol Psychiatry 43:270–277PubMedGoogle Scholar
  114. Mottron L, Burack JA, Iarocci G et al (2003) Locally oriented perception with intact global processing among adolescents with high functioning autism: evidence from multiple paradigms. J Child Psychol Psychiatry 44:904–913PubMedGoogle Scholar
  115. Murphy D, Spooren W (2012) EU-AIMS: a boost to autism research. Nat Rev Drug Discov 11:815–816PubMedGoogle Scholar
  116. Naber FB, Poslawsky IE, van Ijzendoorn MH et al (2013) Brief report: oxytocin enhances paternal sensitivity to a child with autism: a double-blind within-subject experiment with intranasally administered oxytocin. J Autism Dev Disord 43:224–229PubMedCentralPubMedGoogle Scholar
  117. Nelson EK, Piehler B, Eckels J et al (2011) LabKey Server: an open source platform for scientific data integration, analysis and collaboration. BMC Bioinforma 12:71Google Scholar
  118. Nicholson JK, Lindon JC (2008) Metabonomics. Nature 455:1054–1056PubMedGoogle Scholar
  119. Noh HJ, Ponting CP, Boulding HC et al (2013) Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. PLoS Genet 9:e1003523PubMedCentralPubMedGoogle Scholar
  120. O’Hearn K, Asato M, Ordaz S, Luna B (2008) Neurodevelopment and executive function in autism. Dev Psychopathol 20:1103–1132PubMedGoogle Scholar
  121. Orrù G, Pettersson-Yeo W, Marquand AF et al (2012) Using support vector machine to identify imaging biomarkers of neurological and psychiatric disease: a critical review. Neurosci Biobehav Rev 36:1140–1152PubMedGoogle Scholar
  122. Ozyurt IB, Keator DB, Wei D et al (2010) Federated web-accessible clinical data management within an extensible neuroimaging database. Neuroinformatics 8:231–249PubMedCentralPubMedGoogle Scholar
  123. Pan S, Rush J, Peskind ER et al (2008) Application of targeted quantitative proteomics analysis in human cerebrospinal fluid using a liquid chromatography matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometer (LC MALDI TOF/TOF) platform. J Proteome Res 7:720–730PubMedGoogle Scholar
  124. Parner ET, Baron-Cohen S, Lauritsen MB et al (2012) Parental age and autism spectrum disorders. Ann Epidemiol 22:143–150PubMedGoogle Scholar
  125. Peakman TC, Elliott P (2008) The UK Biobank sample handling and storage validation studies. Int J Epidemiol 37(Suppl 1):i2–i6PubMedGoogle Scholar
  126. Persico AM, Bourgeron T (2006) Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 29:349–358PubMedGoogle Scholar
  127. Persico AM, Napolioni V (2013) Autism genetics. Behav Brain Res. doi: 10.1016/j.bbr.2013.06.012
  128. Petrinovic MM, Künnecke B (2013) Neuroimaging endophenotypes in animal models of autism spectrum disorders: lost or found in translation? Psychopharmacology. doi: 10.1007/s00213-013-3200-z
  129. Pickles A, Bolton P, MacDonald H et al (1995) 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 57:717–726PubMedCentralPubMedGoogle Scholar
  130. Pierce K, Muller RA, Ambrose J et al (2001) Face processing occurs outside the fusiform ‘face area’ in autism: evidence from functional MRI. Brain 124:2059–2073PubMedGoogle Scholar
  131. Pierce K, Redcay E (2008) Fusiform function in children with an autism spectrum disorder is a matter of “who”. Biol Psychiatry 64:552–560PubMedCentralPubMedGoogle Scholar
  132. Piven J, Tsai GC, Nehme E et al (1991) Platelet serotonin, a possible marker for familial autism. J Autism Dev Disord 21:51–59PubMedGoogle Scholar
  133. Piven J, Palmer P, Jacobi D et al (1997) Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. Am J Psychiatry 154:185–190PubMedGoogle Scholar
  134. Poelmans G, Franke B, Pauls DL et al (2013) AKAPs integrate genetic findings for autism spectrum disorders. Transl Psychiatry 3:e270PubMedCentralPubMedGoogle Scholar
  135. Poline J-B, Breeze JL, Ghosh S et al (2012) Data sharing in neuroimaging research. Front Neuroinform 6:9PubMedCentralPubMedGoogle Scholar
  136. Prilusky J, Oueillet E, Ulryck N et al (2005) HalX: an open-source LIMS (Laboratory Information Management System) for small- to large-scale laboratories. Acta Crystallogr D Biol Crystallogr 61:671–678PubMedGoogle Scholar
  137. Rayner TF, Rocca-Serra P, Spellman PT et al (2006) A simple spreadsheet-based, MIAME-supportive format for microarray data: MAGE-TAB. BMC Bioinforma 7:489Google Scholar
  138. Reichelt WH, Knivsberg AM, Nodland M et al (1997) Urinary peptide levels and patterns in autistic children from seven countries, and the effect of dietary intervention after 4 years. Dev Brain Dysfunct 10:44–55Google Scholar
  139. Rice K, Moriuchi JM, Jones W, Klin A (2012) Parsing heterogeneity in autism spectrum disorders: visual scanning of dynamic social scenes in school-aged children. J Am Acad Child Adolesc Psychiatry 51:238–248PubMedCentralPubMedGoogle Scholar
  140. Rocca-Serra P, Brandizi M, Maguire E et al (2010) ISA software suite: supporting standards-compliant experimental annotation and enabling curation at the community level. Bioinformatics 26:2354–2356PubMedGoogle Scholar
  141. Rosenthal M, Wallace GL, Lawson R et al (2013) Impairments in real-world executive function increase from childhood to adolescence in autism spectrum disorders. Neuropsychology 27:13–18PubMedGoogle Scholar
  142. Rossi CC, Van de Water J, Rogers SJ et al (2011) Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders. Brain Behav Immun 25:1123–1135PubMedCentralPubMedGoogle Scholar
  143. Rossignol DA, Frye RE (2011) Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol 53:783–792PubMedGoogle Scholar
  144. Rutter M (2005) Incidence of autism spectrum disorders: changes over time and their meaning. Acta Paediatr 94:2–15PubMedGoogle Scholar
  145. Sacco R, Militerni R, Frolli A et al (2007) Clinical, morphological, and biochemical correlates of head circumference in autism. Biol Psychiatry 62:1038–1047PubMedGoogle Scholar
  146. Sacco R, Curatolo P, Manzi B et al (2010) Principal pathogenetic components and biological endophenotypes in autism spectrum disorders. Autism Res 3:237–252PubMedGoogle Scholar
  147. Sacco R, Lenti C, Saccani M et al (2012) Cluster analysis of autistic patients based on principal pathogenetic components. Autism Res 5:137–147PubMedGoogle Scholar
  148. Sansone S-A, Rocca-Serra P, Brandizi M et al (2008) The first RSBI (ISA-TAB) workshop: “Can a simple format work for complex studies?”. OMICS 12:143–149PubMedGoogle Scholar
  149. Sarachana T, Zhou R, Chen G et al (2010) Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines. Genome Med 2:23PubMedCentralPubMedGoogle Scholar
  150. Saresella M, Marventano I, Guerini FR et al (2009) An autistic endophenotype results in complex immune dysfunction in healthy siblings of autistic children. Biol Psychiatry 66:978–984PubMedGoogle Scholar
  151. Schmitz N, Rubia K, Daly E et al (2006) Neural correlates of executive function in autistic spectrum disorders. Biol Psychiatry 59:7–16PubMedGoogle Scholar
  152. Schmitz N, Rubia K, van Amelsvoort T et al (2008) Neural correlates of reward in autism. Br J Psychiatry 192:19–24PubMedGoogle Scholar
  153. Schwarz E, Guest PC, Rahmoune H, Wang L et al (2011) Sex-specific serum biomarker patterns in adults with Asperger’s syndrome. Mol Psychiatry 16:1213–1220PubMedGoogle Scholar
  154. Shih P, Shen M, Ottl B et al (2010) Atypical network connectivity for imitation in autism spectrum disorder. Neuropsychologia 48:2931–2939PubMedCentralPubMedGoogle Scholar
  155. Shtilbans A, Henchcliffe C (2012) Biomarkers in Parkinson’s disease: an update. Curr Opin Neurol 25:460–465PubMedGoogle Scholar
  156. Skafidas E, Testa R, Zantomio D et al (2012) Predicting the diagnosis of autism spectrum disorder using gene pathway analysis. Mol Psychiatry. doi: 10.1038/mp.2012.126
  157. Smith B, Ashburner M, Rosse C et al (2007) The OBO Foundry: coordinated evolution of ontologies to support biomedical data integration. Nat Biotechnol 25:1251–1255PubMedCentralPubMedGoogle Scholar
  158. Spellman PT, Miller M, Stewart J et al (2002) Design and implementation of microarray gene expression markup language (MAGE-ML). Genome Biol 3: RESEARCH0046Google Scholar
  159. Spence SJ, Cantor RM, Chung L et al (2006) Stratification based on language-related endophenotypes in autism: attempt to replicate reported linkage. Am J Med Genet B Neuropsychiatr Genet 141B:591–598PubMedGoogle Scholar
  160. Spezio ML, Adolphs R, Hurley RS et al (2007) Abnormal use of facial information in high-functioning autism. J Autism Dev Disord 37:929–939PubMedGoogle Scholar
  161. Steffenburg S, Gillberg C, Hellgren L et al. (1989) A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 30:405–416Google Scholar
  162. Tachibana M, Kagitani-Shimono K, Mohri I, Yamamoto T et al (2013) Long-term administration of intranasal oxytocin is a safe and promising therapy for early adolescent boys with autism spectrum disorders. J Child Adolesc Psychopharmacol 23:123–127PubMedGoogle Scholar
  163. Tan A, Tripp B, Daley D (2011) BRISK-research-oriented storage kit for biology-related data. Bioinformatics 27:2422–2425PubMedGoogle Scholar
  164. Tesink CMJY, Buitelaar JK, Petersson KM et al (2009) Neural correlates of pragmatic language comprehension in autism spectrum disorders. Brain 132:1941–5192PubMedGoogle Scholar
  165. Tolopko AN, Sullivan JP, Erickson SD et al (2010) Screensaver: an open source lab information management system (LIMS) for high throughput screening facilities. BMC Bioinforma 11:260Google Scholar
  166. Tordjman S, Anderson GM, Bellissant E et al (2012) Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology 37:1990–1997PubMedGoogle Scholar
  167. Tripi G, Roux S, Canziani T et al (2008) Minor physical anomalies in children with autism spectrum disorder. Early Hum Dev 84:217–223PubMedGoogle Scholar
  168. UK Biobank (2007) Protocol for a large-scale prospective epidemiological resource. March 21, 2007. Available via Accessed 12 Apr 2013
  169. van der Zwaag B, Franke L et al (2009) Gene-network analysis identifies susceptibility genes related to glycobiology in autism. PLoS One 4:e5324PubMedCentralPubMedGoogle Scholar
  170. Veenstra-VanderWeele J, Blakely RD (2012) Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology 37:196–212PubMedGoogle Scholar
  171. Voineagu I, Wang X, Johnston P et al (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474:380–384PubMedCentralPubMedGoogle Scholar
  172. Vorstman J, Spooren W, Gee T et al (2013) Autism genetics and how genetic studies can be used in the development of pharmaceutical compounds. Psychopharmacology (in press)Google Scholar
  173. Wallace GL, Happé F, Giedd JN (2009) A case study of a multiply talented savant with an autism spectrum disorder: neuropsychological functioning and brain morphometry. Philos Trans R Soc Lond B Biol Sci 364:1425–1432PubMedGoogle Scholar
  174. Walsh P, Elsabbagh M, Bolton P et al (2011) In search of biomarkers for autism: scientific, social and ethical challenges. Nat Rev Neurosci 12:603–612PubMedGoogle Scholar
  175. Walum H, Lichtenstein P, Neiderhiser JM et al (2012) Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior. Biol Psychiatry 71:419–426PubMedCentralPubMedGoogle Scholar
  176. Wang L, Angley MT, Gerber JP et al (2011) A review of candidate urinary biomarkers for autism spectrum disorder. Biomarkers 16:537–552PubMedGoogle Scholar
  177. Wang L, Li J, Ruan Y et al (2013) Sequencing ASMT identifies rare mutations in Chinese Han patients with autism. PLoS One 8(1):e53727Google Scholar
  178. Weisman O, Zagoory-Sharon O, Feldman R (2012) Oxytocin administration to parent enhances infant physiological and behavioral readiness for social engagement. Biol Psychiatry 72:982–989PubMedGoogle Scholar
  179. Wills S, Rossi CC, Bennett J et al (2011) Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism. Mol Autism 2:5PubMedCentralPubMedGoogle Scholar
  180. Wolff JJ, Gu H, Gerig G et al (2012) Differences in white matter fiber tract development present from 6 to 24 months in infants with autism. Am J Psychiatry 169:589–600PubMedCentralPubMedGoogle Scholar
  181. Yap IK, Angley M, Veselkov KA et al (2010) Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res 9:2996–3004PubMedGoogle Scholar
  182. Young LJ, Wang Z, Insel TR (1998) Neuroendocrine bases of monogamy. Trends Neurosci 21:71–75PubMedGoogle Scholar
  183. Young GS, Merin N, Rogers SJ, Ozonoff S (2009) Gaze behavior and affect at 6-months: predicting clinical outcomes and language development in typically developing infants and infants at-risk for autism. Dev Sci 12:798–814PubMedCentralPubMedGoogle Scholar
  184. Zafeiriou DI, Ververi A, Dafoulis V et al (2013) Autism spectrum disorders: the quest for genetic syndromes. Am J Med Genet B Neuropsychiatr Genet 162:327–366Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Barbara Ruggeri
    • 1
  • Ugis Sarkans
    • 2
  • Gunter Schumann
    • 1
  • Antonio M. Persico
    • 3
    Email author
  1. 1.MRC Social, Genetic and Developmental Psychiatry Centre, Institute of PsychiatryKing’s College LondonLondonUK
  2. 2.European Molecular Biology LaboratoryEuropean Bioinformatics InstituteHinxtonUK
  3. 3.Child and Adolescent NeuroPsychiatry Unit, Laboratory of Molecular Psychiatry & NeurogeneticsUniversity “Campus Bio-Medico”RomeItaly

Personalised recommendations