Endophenotypes in Autism Spectrum Disorders


Autism spectrum disorder (ASD) is a complex disease with onset during early childhood and typically a lifelong course. Genetic liability plays a prominent role in ASD, as siblings of affected individuals display on average 25-fold higher autism risk rates compared to the general population. However, genetic contributions fit in most cases with complex, “multiple-hit,” oligogenic/polygenic models encompassing several loci and also gene-environment interactions. Furthermore, ASD should be viewed as the extreme end of a set of continuous dimensions pertaining to the realms of human socialization, language development, and behavior, rather than as a “black or white” medical condition. This complexity spurs interest into the heuristic potential of “endophenotypes” in ASD, as originally applied by Gottesman and Shields (Br J Psychiatry 122:15–30, 1973) to the realm of psychiatry. Endophenotypes can be defined as familial, heritable, and quantitative traits associated with a complex disease. Occupying an intermediate position between genotype and behavior, these traits offer the potential to bridge the gap between complex disease phenotypes, such as autism, and the underlying genetic mechanisms. The most reliable endophenotypes in ASD can be grouped into seven categories: biochemical, morphological, hormonal, immunological, neurophysiological/neuroanatomical, neuropsychological, and behavioral. Their use holds promise to foster advances not only toward more reliable genotype-phenotype correlations in autism research but also in dissecting clinical subgroups of ASD patients with relatively homogeneous pathophysiological underpinnings, aiding clinicians in early diagnosis once incorporated into broader biomarker panels, and predicting developmental trajectories and treatment response.


Autism Spectrum Disorder Autism Spectrum Disorder Autistic Child Autistic Patient Autistic Individual 
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  1. Adolphs R, Spezio ML, Parlier M, et al. Distinct face-processing strategies in parents of autistic children. Curr Biol. 2008;18:1090–3.PubMedCrossRefGoogle Scholar
  2. Alarcón M, Abrahamas BS, Stone JL, et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet. 2008;82:150–9.PubMedCrossRefGoogle Scholar
  3. Altieri L, Neri C, Sacco R, et al. Urinary p-cresol is elevated in small children with severe autism spectrum disorder. Biomarkers. 2011;16:252–60.PubMedCrossRefGoogle Scholar
  4. Anderson GM, Horne WC, Chatterjee D, et al. The hyperserotonemia of autism. Ann N Y Acad Sci. 1990;600:331–40.PubMedCrossRefGoogle Scholar
  5. Ashwood P, Wills S, Van de Water J, et al. The immune response in autism: a new frontier for autism research. J Leukoc Biol. 2006;80:1–15. [Epub 2006 May 12].PubMedCrossRefGoogle Scholar
  6. Bailey A, Le Couteur A, Gottesman I, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25:63–77.PubMedCrossRefGoogle Scholar
  7. Baron-Cohen S, Scott FJ, Allison C, et al. Prevalence of autism − spectrum conditions: UK school − based population study. Br J Psychiatry. 2009;194:500–9.PubMedCrossRefGoogle Scholar
  8. Belmonte MK, Gomot M, Baron-Cohen S. Visual attention in autism families: ‘unaffected’ sibs share atypical frontal activation. J Child Psychol Psychiatry. 2010;51:259–76.PubMedCrossRefGoogle Scholar
  9. Bradford Y, Haines J, Hutcheson H, et al. Incorporating language phenotypes strengthens evidence of linkage to autism. Am J Med Genet. 2001;105:539–47.PubMedCrossRefGoogle Scholar
  10. Bruneau N, Bonnet-Brilhault F, Gomot M, et al. Cortical auditory processing and communication in children with autism: electrophysiological/behavioral relations. Int J Psychophysiol. 2003;51:17–25.PubMedCrossRefGoogle Scholar
  11. Cass H, Gringras P, March J, et al. Absence of urinary opioid peptides in children with autism. Arch Dis Child. 2008;93:745–50.PubMedCrossRefGoogle Scholar
  12. Cook Jr EH, Leventhal BL, Freedman DX. Free serotonin in plasma: autistic children and their first-degree relatives. Biol Psychiatry. 1988;24:488–91.PubMedCrossRefGoogle Scholar
  13. Cortesi F, Giannotti F, Sebastiani T, et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. J Sleep Res. 2012;21:700. [Epub ahead of print].PubMedCrossRefGoogle Scholar
  14. Courchesne E, Pierce K, Schumann CM, et al. Mapping early brain development in autism. Neuron. 2007;56:399–413.PubMedCrossRefGoogle Scholar
  15. Crino PB. mTOR: a pathogenic signaling pathway in developmental brain malformations. Trends Mol Med. 2011;17:734–42.PubMedCrossRefGoogle Scholar
  16. Croen LA, Braunschweig D, Haapanen L, et al. Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study. Biol Psychiatry. 2008;64:583–8.PubMedCrossRefGoogle Scholar
  17. Dapretto M, Davies MS, Pfeifer JH, et al. Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders. Nat Neurosci. 2006;9:28–30.PubMedCrossRefGoogle Scholar
  18. Delorme R, Goussé V, Roy I, et al. Shared executive dysfunctions in unaffected relatives of patients with autism and obsessive-compulsive disorder. Eur Psychiatry. 2007;22:32–8.PubMedCrossRefGoogle Scholar
  19. Dettmer K, Hanna D, Whetstone P, et al. 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. 2007;388:1643–51.PubMedCrossRefGoogle Scholar
  20. Ecker C, Marquand A, Mourão-Miranda J, et al. Describing the brain in autism in five dimensions–magnetic resonance imaging-assisted diagnosis of autism spectrum disorder using a multiparameter classification approach. J Neurosci. 2010;30:10612–23.PubMedCrossRefGoogle Scholar
  21. Ecker C, Suckling J, Deoni SC, et al. Brain anatomy and its relationship to behavior in adults with autism spectrum disorder: a multicenter magnetic resonance imaging study. Arch Gen Psychiatry. 2012;69:195–209.PubMedCrossRefGoogle Scholar
  22. Feldman R. Oxytocin and social affiliation in humans. Horm Behav. 2012;61:380–91.PubMedCrossRefGoogle Scholar
  23. Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65:591–8.PubMedCrossRefGoogle Scholar
  24. Goines P, Haapanen L, Boyce R, et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav Immun. 2011;25:514–23.PubMedCrossRefGoogle Scholar
  25. Gomot M, Belmonte MK, Bullmore ET, et al. Brain hyper-reactivity to auditory novel targets in children with high-functioning autism. Brain. 2008;131:2479–88.PubMedCrossRefGoogle Scholar
  26. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636–45.PubMedCrossRefGoogle Scholar
  27. Gottesman II, Shields J. Genetic theorizing and schizophrenia. Br J Psychiatry. 1973;122:15–30.PubMedCrossRefGoogle Scholar
  28. Grether JK, Rosen NJ, Smith KS, et al. Investigation of shifts in autism reporting in the California Department of Developmental Services. J Autism Dev Disord. 2009;39:1412–9.PubMedCrossRefGoogle Scholar
  29. Hallmayer J, Cleveland S, Torres A, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68:1095–102.PubMedCrossRefGoogle Scholar
  30. Hammock E, Veenstra-Vanderweele J, Yan Z, et al. Examining autism spectrum disorders by biomarkers: example from the oxytocin and serotonin systems. J Am Acad Child Adolesc Psychiatry. 2012;51:712–21.PubMedCrossRefGoogle Scholar
  31. Hammond P, Forster-Gibson C, Chudley AE, et al. Face-brain asymmetry in autism spectrum disorders. Mol Psychiatry. 2008;13:614–23.PubMedCrossRefGoogle Scholar
  32. Hertz-Picciotto I, Delwiche L. The rise in autism and the role of age at diagnosis. Epidemiology. 2009;20:84–90.PubMedCrossRefGoogle Scholar
  33. Hollander E, Bartz J, Chaplin W, et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry. 2007;61:498–503.PubMedCrossRefGoogle Scholar
  34. Hunter LC, O’Hare A, Herron WJ, et al. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2003;45:121–8.PubMedCrossRefGoogle Scholar
  35. John B, Lewis KR. Chromosome variability and geographic distribution in insects. Science. 1966;152:711–21.PubMedCrossRefGoogle Scholar
  36. Kaiser MD, Hudac CM, Shultz S, et al. Neural signatures of autism. Proc Natl Acad Sci U S A. 2010;107:21223–8.PubMedCrossRefGoogle Scholar
  37. Katsui T, Okuda M, Usuda S, et al. Kinetics of3 H-serotonin uptake by platelets in infantile autism and developmental language disorder (including five pairs of twins). J Autism Dev Disord. 1986;16:69–76.PubMedCrossRefGoogle Scholar
  38. King M, Bearman P. Diagnostic change and the increased prevalence of autism. Int J Epidemiol. 2009;38:1224–34.PubMedCrossRefGoogle Scholar
  39. Lesch KP, Wolozin BL, Murphy DL, et al. Primary structure of the human platelet serotonin (5-HT) uptake site: identity with the brain 5-HT transporter. J Neurochem. 1993;60:2319–22.PubMedCrossRefGoogle Scholar
  40. Liu XQ, Paterson AD, Szatmari P, et al. Genome-wide linkage analyses of quantitative and categorical autism subphenotypes. Biol Psychiatry. 2008;64:561–70.PubMedCrossRefGoogle Scholar
  41. Lucht MJ, Barnow S, Sonnenfeld C, et al. Associations between the oxytocin receptor gene (OXTR) and affect, loneliness and intelligence in normal subjects. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Aug 1;33:860–866.PubMedCrossRefGoogle Scholar
  42. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10:307–18.PubMedCrossRefGoogle Scholar
  43. Marazziti D, Muratori F, Cesari A, et al. Increased density of the platelet serotonin transporter in autism. Pharmacopsychiatry. 2000;33:165–8.PubMedCrossRefGoogle Scholar
  44. McBride PA, Anderson GM, Hertzig ME, et al. Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry. 1998;37:767–76.PubMedCrossRefGoogle Scholar
  45. Melke J, Goubran Botros H, Chaste P, et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry. 2008;13:90–8.PubMedCrossRefGoogle Scholar
  46. Miles JH, Hadden LL, Takahashi TN, et al. Head circumference is an independent clinical finding associated with autism. Am J Med Genet. 2000;95:339–50.PubMedCrossRefGoogle Scholar
  47. Modahl C, Green L, Fein D, et al. Plasma oxytocin levels in autistic children. Biol Psychiatry. 1998;43:270–7.PubMedCrossRefGoogle Scholar
  48. Persico AM. Autisms. In: Rakic P, Rubenstein J, editors. Comprehensive developmental neuroscience. San Diego: Elsevier; 2012.Google Scholar
  49. Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 2006;29:349–58.PubMedCrossRefGoogle Scholar
  50. Piven J, Tsai GC, Nehme E, et al. Platelet serotonin, a possible marker for familial autism. J Autism Dev Disord. 1991;21:51–9.PubMedCrossRefGoogle Scholar
  51. Piven J, Palmer P, Jacobi D, et al. Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. Am J Psychiatry. 1997;154:185–90.PubMedGoogle Scholar
  52. Reichelt WH, Knivsberg AM, Nodland M, et al. Urinary peptide levels and patterns in autistic children from seven countries, and the effect of dietary intervention after 4 years. Dev Brain Dysfunct. 1997;10:44–55.Google Scholar
  53. Rossi CC, Van de Water J, Rogers SJ, et al. Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders. Brain Behav Immun. 2011;25:1123–35.PubMedCrossRefGoogle Scholar
  54. Rossignol DA, Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol. 2011;53:783–92.PubMedCrossRefGoogle Scholar
  55. Rutter M. Incidence of autism spectrum disorders: changes over time and their meaning. Acta Paediatr. 2005;94:2–15.PubMedCrossRefGoogle Scholar
  56. Sacco R, Militerni R, Frolli A, et al. Clinical, morphological, and biochemical correlates of head circumference in autism. Biol Psychiatry. 2007;62:1038–47.PubMedCrossRefGoogle Scholar
  57. Sacco R, Curatolo P, Manzi B, et al. Principal pathogenetic components and biological endophenotypes in autism spectrum disorders. Autism Res. 2010;3:237–52.PubMedCrossRefGoogle Scholar
  58. Sacco R, Lenti C, Saccani M, et al. Cluster analysis of autistic patients based on principal pathogenetic components. Autism Res. 2012;5:137–47.PubMedCrossRefGoogle Scholar
  59. Saresella M, Marventano I, Guerini FR, et al. An autistic endophenotype results in complex immune dysfunction in healthy siblings of autistic children. Biol Psychiatry. 2009;66:978–84.PubMedCrossRefGoogle Scholar
  60. Spence SJ, Cantor RM, Chung L, et al. Stratification based on language-related endophenotypes in autism: attempt to replicate reported linkage. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:591–8.PubMedCrossRefGoogle Scholar
  61. Spezio ML, Adolphs R, Hurley RS, et al. Abnormal use of facial information in high-functioning autism. J Autism Dev Disord. 2007;37:929–39.PubMedCrossRefGoogle Scholar
  62. Steffenburg S, Gillberg C, Hellgren L, et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry. 1989;30:405–16.PubMedCrossRefGoogle Scholar
  63. Tordjman S, Anderson GM, Bellissant E, et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology. 2012;37(12):1990. [Epub ahead of print].PubMedCrossRefGoogle Scholar
  64. Tripi G, Roux S, Canziani T, et al. Minor physical anomalies in children with autism spectrum disorder. Early Hum Dev. 2008;84:217–23.PubMedCrossRefGoogle Scholar
  65. Tropea D, Giacometti E, Wilson NR, et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci U S A. 2009;106:2029–34.PubMedCrossRefGoogle Scholar
  66. Veenstra-VanderWeele J, Blakely RD. Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology. 2012;37:196–212.PubMedCrossRefGoogle Scholar
  67. Wallace GL, Happé F, Giedd JN. 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. 2009;364:1425–32.PubMedCrossRefGoogle Scholar
  68. Walsh P, Elsabbagh M, Bolton P, et al. In search of biomarkers for autism: scientific, social and ethical challenges. Nat Rev Neurosci. 2011;12:603–12.PubMedCrossRefGoogle Scholar
  69. Walum H, Lichtenstein P, Neiderhiser JM, et al. Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior. Biol Psychiatry. 2012;71:419–26.PubMedCrossRefGoogle Scholar
  70. Wang L, Angley MT, Gerber JP, et al. A review of candidate urinary biomarkers for autism spectrum disorder. Biomarkers. 2011;16:537–52.PubMedCrossRefGoogle Scholar
  71. Weisman O, Zagoory-Sharon O, Feldman R. Oxytocin administration to parent enhances infant physiological and behavioral readiness for social engagement. Biol Psychiatry. 2012;72:982. [Epub ahead of print].PubMedCrossRefGoogle Scholar
  72. Wills S, Rossi CC, Bennett J, et al. Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism. Mol Autism. 2011;2:5.PubMedCrossRefGoogle Scholar
  73. Yap IK, Angley M, Veselkov KA, et al. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010;9:2996–3004.PubMedCrossRefGoogle Scholar
  74. Young LJ, Wang Z, Insel TR. Neuroendocrine bases of monogamy. Trends Neurosci. 1998;21:71–5.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Unit of Child and Adolescent PsychiatryUniversity “Campus Bio-Medico”RomeItaly
  2. 2.Laboratory of Molecular Psychiatry and NeurogeneticsUniversity “Campus Bio-Medico”RomeItaly

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