Original Article | Published:

Sex-specific serum biomarker patterns in adults with Asperger's syndrome

Molecular Psychiatry volume 16, pages 12131220 (2011) | Download Citation

Abstract

Autism spectrum conditions have been hypothesized to be an exaggeration of normal male low-empathizing and high-systemizing behaviors. We tested this hypothesis at the molecular level by performing comprehensive multi-analyte profiling of blood serum from adult subjects with Asperger's syndrome (AS) compared with controls. This led to identification of distinct sex-specific biomarker fingerprints for male and female subjects. Males with AS showed altered levels of 24 biomarkers including increased levels of cytokines and other inflammatory molecules. Multivariate statistical classification of males using this panel of 24 biomarkers revealed a marked separation between AS and controls with a sensitivity of 0.86 and specificity of 0.88. Testing this same panel in females did not result in a separation between the AS and control groups. In contrast, AS females showed altered levels of 17 biomarkers including growth factors and hormones such as androgens, growth hormone and insulin-related molecules. Classification of females using this biomarker panel resulted in a separation between AS and controls with sensitivities and specificities of 0.96 and 0.83, respectively, and testing this same panel in the male group did not result in a separation between the AS and control groups. The finding of elevated testosterone in AS females confirmed predictions from the ‘extreme male brain’ and androgen theories of autism spectrum conditions. We conclude that to understand the etiology and development of autism spectrum conditions, stratification by sex is essential.

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References

  1. 1.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental disorders. 4th Edition Text Revision: DSM-IV-TR (2000). ISBN: 0890420256.

  2. 2.

    , , . Autism and autism spectrum disorders: diagnostic issues for the coming decade. J Child Psychol Psychiatry 2009; 50: 108–115.

  3. 3.

    , , , , , et al. Prevalence of autism-spectrum conditions: UK school-based population study. Br J Psychiatry 2009; 194: 500–509.

  4. 4.

    . Asperger's syndrome: a clinical account. Psychol Med 1981; 11: 115–129.

  5. 5.

    . The extreme male brain theory of autism. Trends Cogn Sci 2002; 6: 248–254.

  6. 6.

    , , . Sex-typical play: masculinization/defeminization in girls with an autism spectrum condition. J Autism Dev Disord 2008; 38: 1028–1035.

  7. 7.

    , , . Sex differences in the brain: implications for explaining autism. Science 2005; 310: 819–823.

  8. 8.

    , , , , , . Fetal testosterone and autistic traits. Br J Psychol 2009; 100(Pt 1): 1–22.

  9. 9.

    , , , , , . Foetal testosterone and the child systemizing quotient. Eur J Endocrinol 2006; 155(suppl_1): S123.

  10. 10.

    , , , , , . Fetal testosterone and empathy: evidence from the empathy quotient (EQ) and the ‘reading the mind in the eyes’ test. Soc Neurosci 2006; 1: 135–148.

  11. 11.

    , , , . Elevated rates of testosterone-related disorders in women with autism spectrum conditions. Horm Behav 2007; 51: 597–604.

  12. 12.

    , , , . The 2nd to 4th digit ratio and autism. Dev Med Child Neurol 2001; 43: 160–164.

  13. 13.

    , , , , , et al. Possible association between the androgen receptor gene and autism spectrum disorder. Psychoneuroendocrinology 2009; 34: 752–761.

  14. 14.

    , , , . Study of HOXD genes in autism particularly regarding the ratio of second to fourth digit length. Brain Dev 2009; 32: 356–361.

  15. 15.

    , , , , , et al. Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Autism Res 2009; 2: 157–177.

  16. 16.

    , , . Evidence of brain overgrowth in the first year of life in autism. JAMA 2003; 290: 337–344.

  17. 17.

    , , , , , et al. Autism and immunity: revisited study. Int J Immunopathol Pharmacol 2009; 22: 15–19.

  18. 18.

    , , , , , et al. Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15. J Neuroimmunol 2008; 205: 148–154.

  19. 19.

    , , . Autoimmunity in autism. Curr Opin Investig Drugs 2009; 10: 463–473.

  20. 20.

    , , , , , et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Standards for Reporting of Diagnostic Accuracy. Clin Chem 2003; 49: 1–6.

  21. 21.

    , , , , . The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord 2001; 31: 5–17.

  22. 22.

    , , , , , et al. Predicting Autism Spectrum Quotient (AQ) from the Systemizing Quotient-Revised (SQ-R) and Empathy Quotient (EQ). Brain Res 2006; 1079: 47–56.

  23. 23.

    , , , . The Autism-Spectrum Quotient (AQ) in Japan: a cross-cultural comparison. J Autism Dev Disord 2006; 36: 263–270.

  24. 24.

    , , , . Factor structure, reliability and criterion validity of the Autism-Spectrum Quotient (AQ): a study in Dutch population and patient groups. J Autism Dev Disord 2008; 38: 1555–1566.

  25. 25.

    , , , . Screening adults for Asperger Syndrome using the AQ: a preliminary study of its diagnostic validity in clinical practice. J Autism Dev Disord 2005; 35: 331–335.

  26. 26.

    , , , , , . Using self-report to identify the broad phenotype in parents of children with autistic spectrum disorders: a study using the Autism-Spectrum Quotient. J Child Psychol Psychiatry 2004; 45: 1431–1436.

  27. 27.

    , , , , , et al. Multianalyte profiling of serum antigens and autoimmune and infectious disease molecules to identify biomarkers dysregulated in epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 2008; 17: 2872–2881.

  28. 28.

    . No adjustments are needed for multiple comparisons. Epidemiology 1990; 1: 43–46.

  29. 29.

    , , . The Elements of Statistical Learning. Springer-Verlag: New York, 2003.

  30. 30.

    , , , , , . The effects of GH replacement in adult GH-deficient patients: changes in body composition without concomitant changes in the adipokines and insulin resistance. Clin Endocrinol (Oxf) 2004; 60: 442–450.

  31. 31.

    , , , , , et al. Increased levels of circulating insulin-related peptides in first onset, antipsychotic naïve schizophrenia patients. Mol Psychiatry 2010; 15: 118–119.

  32. 32.

    , , . Testosterone inhibits immunoglobulin production by human peripheral blood mononuclear cells. Clin Exp Immunol 1996; 106: 410–415.

  33. 33.

    , , , , , et al. Acceleration of luteinizing hormone pulse frequency in adolescent girls with a history of central precocious puberty with versus without hyperandrogenism. Horm Res 2007; 68: 278–285.

  34. 34.

    , , . Mechanisms of hypothalamic-pituitary-gonadal disruption in polycystic ovarian syndrome. Arch Med Res 2001; 32: 544–552.

  35. 35.

    , , . Growth hormone deficit in autism. J Autism Dev Disord 1993; 23: 421–422.

  36. 36.

    , , , , , et al. Elevated levels of growth-related hormones in autism and autism spectrum disorder. Clin Endocrinol (Oxf) 2007; 67: 230–237.

  37. 37.

    , , . Low levels of insulin-like growth factor-I in cerebrospinal fluid in children with autism. Dev Med Child Neurol 2001; 43: 614–616.

  38. 38.

    , , , , . Comparison of four different treatment regimens on coagulation parameters, hormonal and metabolic changes in women with polycystic ovary syndrome. Arch Gynecol Obstet; 28 March 2009 [e-pub ahead of print].

  39. 39.

    , , , , , . Glucose and insulin components of the metabolic syndrome are associated with hyperandrogenism in postmenopausal women: the atherosclerosis risk in communities study. Am J Epidemiol 2004; 160: 540–548.

  40. 40.

    , , , . Effect of rosiglitazone on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Zhonghua Fu Chan Ke Za Zhi 2002; 37: 271–273.

  41. 41.

    , , . Autism and the immune system. J Child Psychol Psychiatry 1997; 38: 337–349.

  42. 42.

    , , , , , et al. Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol 2006; 172: 198–205.

  43. 43.

    , , , , , et al. Identifying blood biomarkers for mood disorders using convergent functional genomics. Mol Psychiatry 2009; 14: 156–174.

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Acknowledgements

This work was funded by the Stanley Medical Research Institute, Psynova Neurotech and the Three Guineas Project Grant, Cambridge Lifespan Asperger Syndrome Service. Insulin-related assays were performed by Keith Burling at the NIHR Cambridge Biomedical Research Centre, Core Biochemistry Assay Laboratory, Addenbrookes Hospital, Cambridge, UK.

Author information

Affiliations

  1. Institute of Biotechnology, University of Cambridge, Cambridge, UK

    • E Schwarz
    • , P C Guest
    • , H Rahmoune
    • , L Wang
    • , Y Levin
    •  & S Bahn
  2. Department of Psychiatry, Autism Research Centre, University of Cambridge, Cambridge, UK

    • E Ingudomnukul
    • , L Ruta
    • , L Kent
    •  & S Baron-Cohen
  3. Division of Child Neurology and Psychiatry, Department of Pediatrics, University of Catania, Catania, Italy

    • L Ruta
  4. Bute Medical School, University of St Andrews, Scotland, UK

    • L Kent
  5. Rule Based Medicine, Austin, TX, USA

    • M Spain
  6. Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands

    • S Bahn

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The authors declare no conflict of interest.

Corresponding authors

Correspondence to S Baron-Cohen or S Bahn.

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DOI

https://doi.org/10.1038/mp.2010.102

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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