Behavior Genetics

, Volume 37, Issue 1, pp 51–60 | Cite as

Endophenotype Approach to Developmental Psychopathology: Implications for Autism Research

  • Essi VidingEmail author
  • Sarah-Jayne Blakemore
Original Paper


This paper discusses the utility of the endophenotype approach in the study of developmental psychopathology. It is argued that endophenotype research holds considerable promise for the study of gene-brain/cognition-behaviour pathways for developmental disorders. This paper outlines the criteria for determining useful endophenotypes. Possible endophenotypes for autism are discussed as an example of an area where endophenotype research on developmental disorders may be fruitful. It is concluded that although the endophenotype approach holds promise for the study of gene-brain/cognition-behaviour pathways, much work remains to be done in order to validate endophenotype measures. It is also noted that the changing nature of any developmental psychopathology poses a particular challenge to this type of research.


Intermediate phenotype Cognitive development Autism Asperger syndrome Theory of mind Mentalising Central coherence 


  1. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. (DSM-IV). Washington DC, APAGoogle Scholar
  2. Asherson P, IMAGE Consortium (2004) Eur Child Adolescent Psychiat 13(Suppl 1):I50–70Google Scholar
  3. Bailey A et al (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63–77PubMedCrossRefGoogle Scholar
  4. Baron-Cohen S, Wheelwright S, Hill J, Raste Y, Plumb I (2001) The “Reading the Mind in the Eyes” Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiat Allied Disciplines 42(2):241–251Google Scholar
  5. Baron-Cohen S, Leslie AM, Frith U (1985) Does the autistic child have a "theory of mind"? Cognition 21(1):37–46PubMedCrossRefGoogle Scholar
  6. Blakemore S-J, Frith CD (2000) Functional neuroimaging studies of Schizophrenia. In: Mazziotta JC, Toga AW, Frackowiak RSJ (eds) Brain mapping: the disorders. Academic PressGoogle Scholar
  7. Blasi G, Mattay VS, Bertolino, Elvevag AB, Callicott JH, Das S, Kolachana BS, Egan MF, Goldberg TE, Weinberger DR (2005) Effect of catechol-O-methyltransferase val158met genotype on attentional control. J Neurosci: The Official J Soc Neurosci 25(20):5038–5045Google Scholar
  8. 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 Psychiat 42(3):309–316PubMedCrossRefGoogle Scholar
  9. Bruder GE, Keilp JG, Xu H, Shikhman M, Schori E, Gorman JM, Gilliam TC (2005) Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. Biol Psychiat 58(11):901–907PubMedCrossRefGoogle Scholar
  10. Burnette CP, Mundy PC, Meyer JA, Sutton SK, Vaughan AE, Charak D (2005) Weak central coherence and its relations to theory of mind and anxiety in autism. J Autism Develop Disorders 35(1):63–73CrossRefGoogle Scholar
  11. Castellanos FX, Sonuga-Barke EJ, Milham MP, Tannock R (2006) Characterizing cognition in ADHD: beyond executive dysfunction. Trends Cognitive Sci 10(3):117–123CrossRefGoogle Scholar
  12. Castelli F, Frith C, Happe F, Frith U (2002) Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes. Brain 125:1839–1849PubMedCrossRefGoogle Scholar
  13. Dapretto M, Davies MS, Pfeifer JH, Scott AA, Sigman M, Bookheimer SY, Iacoboni M (2006) Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders. Nature Neurosci 9(1):28–30PubMedCrossRefGoogle Scholar
  14. DeGeus EJC, Boomsma DI (2001) A genetic neuroscience approach to human cognition. Eur Psychologist 6:241–253CrossRefGoogle Scholar
  15. Dennett DC (1987) The Intentional Stance. Bradford Books, MIT Press, USAGoogle Scholar
  16. Fombonne E (2005) Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiat 66(Suppl 10):3–8Google Scholar
  17. Frith U, Frith CD (2003) Development and neurophysiology of mentalizing. Phil Trans Roy Soc London. Series B, Biol Sci 358:459–473CrossRefGoogle Scholar
  18. Frith U (2003) Autism: explaining the enigma. BlackwellGoogle Scholar
  19. Frith CD, Frith U (2006) The neural basis of mentalizing. Neuron 50(4):531–534PubMedCrossRefGoogle Scholar
  20. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiat 160(4):636–645PubMedCrossRefGoogle Scholar
  21. Gottesman II, Shields J (1972) Schizophrenia and genetics: a twin vantage point. Academic Press, New YorkGoogle Scholar
  22. 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 Psychiat 42(3):299–307PubMedCrossRefGoogle Scholar
  23. Happé F (1999) Autism: cognitive deficit or cognitive style? Trends in Cognitive Sci 3(6):216–222CrossRefGoogle Scholar
  24. Happe F, Frith U (2006) The weak coherence account: detail-focused cognitive style in autism spectrum disorders. J Autism Develop Disorders 36(1):5–25CrossRefGoogle Scholar
  25. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297:400–3PubMedCrossRefGoogle Scholar
  26. Hariri AR, Weinberger DR (2003) Imaging genomics. Brit Med Bull 65:259–270PubMedCrossRefGoogle Scholar
  27. Hughes C, Adlam A, Happe F, Jackson J, Taylor A, Caspi A (2000) Good test–retest reliability for standard and advanced false-belief tasks across a wide range of abilities. J Child Psychol Psychiat 41(4):483–490PubMedCrossRefGoogle Scholar
  28. Hughes C, Jaffee SR, Happe F, Taylor A, Caspi A, Moffitt TE (2005) Origins of individual differences in theory of mind: from nature to nurture? Child Develop 76(2):356–370PubMedCrossRefGoogle Scholar
  29. Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR, Rodier PM (2000) Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology 62(6):393–405PubMedCrossRefGoogle Scholar
  30. Jolliffe T, Baron-Cohen S (1999) A test of central coherence theory: linguistic processing in high-functioning adults with autism or Asperger syndrome: is local coherence impaired? Cognition 71(2):149–185PubMedCrossRefGoogle Scholar
  31. Joseph RM, Tager-Flusberg H (2004) The relationship of theory of mind and executive functions to symptom type and severity in children with autism. Develop Psychopathol 16(1):137–155CrossRefGoogle Scholar
  32. Klin A, Jones W, Schultz R, Volkmar F, Cohen D (2002a) Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism. Archives General Psychiat 59(9):809–816CrossRefGoogle Scholar
  33. Klin A, Jones W, Schultz R, Volkmar F, Cohen D (2002b) Defining and quantifying the social phenotype in autism. Am J Psychiat 159(6):895–908PubMedCrossRefGoogle Scholar
  34. Kuntsi J, Andreou P, Ma J, Borger NA, van den Meere J (2005) Testing assumptions for endophenotype studies in ADHD: Reliability and validity of tasks in a general population sample. BioMed Central Psychiat 5:40Google Scholar
  35. Lamb JA, Moore J, Bailey A, Monaco AP (2000) Autism: recent molecular genetic advances. Human Mol Genet 9(6):861–868CrossRefGoogle Scholar
  36. Lamb JA, Parr JR, Bailey AJ, Monaco AP (2002). Autism: in search of susceptibility genes. Neuromol Med 2(1):11–28CrossRefGoogle Scholar
  37. Lopez B, Leekam SR (2003) Do children with autism fail to process information in context? J Child Psychol Psychiat Allied Disciplines 44(2):285–300Google Scholar
  38. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Nat Acad Sci USA 100:6186–6191PubMedCrossRefGoogle Scholar
  39. Meyer-Lindenberg A, Buckholtz JW, Kolachana B, Hariri AR, Pezawas L, Blasi G, Wabnitz A, Honea R, Verchinski B, Callicott JH, Egan M, Mattay V, Weinberger DR (2006a) Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc Nat Acad Sci USA 103(16):6269–6274CrossRefGoogle Scholar
  40. Meyer-Lindenberg A, Mervis CB, Faith Berman K (2006b) Neural mechanisms in Williams syndrome: a unique window to genetic influences on cognition and behaviour. Nature Reviews Neuroscience 7:380–393CrossRefGoogle Scholar
  41. Moffitt TE, Caspi A, Rutter M (2005) Strategy for investigating interactions between measured genes and measured environments. Archives General Psychiat 62(5):473–481CrossRefGoogle Scholar
  42. Morton J (2004) Developmental disorders: a causal modelling approach. Blackwell, Oxford, UKGoogle Scholar
  43. Ohnishi T, Hashimoto R, Mori T, Nemoto K, Moriguchi Y, Iida H, Noguchi H, Nakabayashi T, Hori H, Ohmori M, Tsukue R, Anami K, Hirabayashi N, Harada S, Arima K, Saitoh O, Kunugi H (2006) The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia. Brain 129(Pt 2):399–410PubMedGoogle Scholar
  44. Pellicano E, Maybery M, Durkin K, Maley A (2006) Multiple cognitive capabilities/deficits in children with an autism spectrum disorder: “weak” central coherence and its relationship to theory of mind and executive control. Develop psychopathol 18(1):77–98CrossRefGoogle Scholar
  45. Plomin R, Owen MJ, McGuffin P (1994) The genetic basis of complex human behaviors. Science 264:1733–1739PubMedCrossRefGoogle Scholar
  46. Plomin R (2005). Finding genes in child psychology and psychiatry: when are we going to be there? J Child Psychol Psychiat 46(10):1030–1038PubMedCrossRefGoogle Scholar
  47. Premack, Woodruff (1978) Does the chimpanzee have a theory of mind? Behav Brain Sci 1:515–526CrossRefGoogle Scholar
  48. Roffman JL, Weiss AP, Goff DC, Rauch SL, Weinberger DR (2006) Neuroimaging-genetic paradigms: a new approach to investigate the pathophysiology and treatment of cognitive deficits in schizophrenia. Harvard Rev Psychiat 14(2):78–91CrossRefGoogle Scholar
  49. Ronald A, Happe F, Plomin R (2005) The genetic relationship between individual differences in social and nonsocial behaviours characteristic of autism. Develop Sci 8:444–458CrossRefGoogle Scholar
  50. Rutter M, Genetic studies of autism: from the 1970s into the millennium. J Abnorm Child Psychol. 2000 28(1):3–14Google Scholar
  51. Tager-Flusberg H, Sullivan K (1994) A second look at second-order belief attribution in autism. Journal of Autism and Developmental Disorders 24(5):577–586PubMedCrossRefGoogle Scholar
  52. Tunbridge EM, Harrison PJ, Weinberger DR (2006). Catechol-o-Methyltransferase, Cognition, and Psychosis: Val(158)Met and Beyond. Biol Psychiatry 60(2):141–151PubMedGoogle Scholar
  53. Williams JH, Waiter GD, Gilchrist A, Perrett DI, Murray AD, Whiten A (2006) Neural mechanisms of imitation and ‘mirror neuron’ functioning in autistic spectrum disorder. Neuropsychologia 44(4):610–621PubMedCrossRefGoogle Scholar
  54. Wimmer H, Perner J (1983) Beliefs about beliefs: representation and constraining function of wrong beliefs in young children’s understanding of deception. Cognition 13(1):103–128PubMedCrossRefGoogle Scholar
  55. Wing L, Potter D (2002) The epidemiology of autistic spectrum disorders: Is the Prevalence rising? Mental Retardation Develop Disabilities Res Rev 8(3):151–161CrossRefGoogle Scholar
  56. Wing L (1996) Autistic spectrum disorders. Brit Med J 312:327–328PubMedGoogle Scholar
  57. Yirmiya N, Shulman C (1996) Seriation, conservation, and theory of mind abilities in individuals with autism, individuals with mental retardation, and normally developing children. Child Develop 67(5):2045–2059PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of PsychologyUniversity College LondonLondonUK
  2. 2.Institute of Cognitive NeuroscienceUniversity College LondonLondonUK

Personalised recommendations