Skip to main content
Log in

Associations Between the 2nd to 4th Digit Ratio and Autism Spectrum Disorder in Population-Based Samples of Boys and Girls: Findings from the Study to Explore Early Development

  • Original Paper
  • Published:
Journal of Autism and Developmental Disorders Aims and scope Submit manuscript

Abstract

The ratio of the index (2nd) finger to ring (4th) finger lengths (2D:4D) is a proxy for fetal testosterone and estradiol. Studies suggesting 2D:4D is inversely associated with autism spectrum disorder (ASD) in males were limited by lack of confounder and subgroup assessments. Studies of females are sparse. We examined associations between ASD and 2D:4D among children in the Study to Explore Early Development; we considered case subgroups and numerous potential demographic and maternal-perinatal health confounders. We observed a modest inverse association between ASD and right-hand 2D:4D in males; subgroup analyses indicated associations were limited to ASD cases with birth defects/genetic syndromes or dysmorphic features. We observed a positive association between ASD and left-hand 2D:4D in females, overall and within most case subgroups.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abbott, A. D., Colman, R. J., Tiefenthaler, R., Dumesic, D. A., & Abbott, D. H. (2012). Early-to-mid gestation fetal testosterone increases right hand 2D:4D finger length ratio in polycystic ovary syndrome-like monkeys. PLoS ONE, 7(8), e42372. https://doi.org/10.1371/journal.pone.0042372.

    Article  PubMed  PubMed Central  Google Scholar 

  • Al-Zaid, F. S., Alhader, A. A., & Al-Ayadhi, L. Y. (2015). The second to fourth digit ratio (2D:4D) in Saudi boys with autism: A potential screening tool. Early Human Development, 91(7), 413–415.

    Article  PubMed  Google Scholar 

  • Arndt, T. L., Stodgell, C. J., & Rodier, P. M. (2005). The teratology of autism. International Journal of Developmental Neuroscience, 23(2–3), 189–199.

    Article  PubMed  Google Scholar 

  • Barona, M., Kothari, R., Skuse, D., & Micali, N. (2015). Social communication and emotion difficulties and second to fourth digit ratio in a large community-based sample. Molecular Autism, 6, 68. https://doi.org/10.1186/s13229-015-0063-7.

    Article  PubMed  PubMed Central  Google Scholar 

  • Baron-Cohen, S., Auyeung, B., Nørgaard-Pedersen, B., et al. (2015). Elevated fetal steroidogenic activity in autism. Molecular Psychiatry, 20(3), 369–376.

    Article  PubMed  Google Scholar 

  • Baron-Cohen, S., Lombardo, M. V., Auyeung, B., Ashwin, E., Chakrabarti, B., & Knickmeyer, R. (2011). Why are autism spectrum conditions more prevalent in males? PLoS Biology, 9(6), e1001081. https://doi.org/10.1371/journal.pbio.1001081.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bejerot, S., Eriksson, J. M., Bonde, S., Carlström, K., Humble, M. B., & Eriksson, E. (2012). The extreme male brain revisited: Gender coherence in adults with autism spectrum disorder. British Journal of Psychiatry, 201, 116–123.

    Article  PubMed  Google Scholar 

  • Blumberg, S. J., Bramlett, M. D., Kogan, M. D., Schieve, L. A., Jones, J. R., & Lu, M. C. (2013). Changes in prevalence of parent-reported autism spectrum disorder in school-aged U.S. children: 2007 to 2011-2012. National Health Statistics Report, 65, 1–11.

    Google Scholar 

  • Chapman, E., Baron-Cohen, S., Auyeung, B., Knickmeyer, R., Taylor, K., & Hackett, G. (2006). Fetal testosterone and empathy: evidence from the empathy quotient (EQ) and the “reading the mind in the eyes” test. Social Neuroscience, 1(2), 136–148.

    Article  Google Scholar 

  • Christensen, D. L., Baio, J., Braun, K. V., et al. (2016) Prevalence and characteristics of autism spectrum disorder among children aged 8 years—Autism and developmental disabilities monitoring network, 11 sites, United States, 2012. Morbidly and Mortality Weekly Report Surveillance Summary, 65(SS-3), pp. 1–23.

    Google Scholar 

  • de Bruin, E. I., Verheij, F., Wiegman, T., & Ferdinand, R. F. (2006). Differences in finger length ratio between males with autism, pervasive developmental disorder-not otherwise specified, ADHD, and anxiety disorders. Developmental Medicine and Child Neurology, 48(12), 962–965.

    Article  PubMed  Google Scholar 

  • Dela Cruz, C., & Pereira, O. C. (2012). Prenatal testosterone supplementation alters puberty onset, aggressive behavior, and partner preference in adult male rats. The Journal of Physiological Sciences, 62(2), 123–131.

    Article  PubMed  Google Scholar 

  • Dumesic, D. A., Goodarzi, M. O., Chazenbalk, G. D., & Abbott, D. H. (2014). Intrauterine environment and polycystic ovary syndrome. Seminars in Reproductive Medicine, 32(3), 159–165.

    Article  PubMed  PubMed Central  Google Scholar 

  • Falter, C. M., Plaisted, K. C., & Davis, G. (2008). Visuo-spatial processing in autism—Testing the predictions of extreme male brain theory. Journal of Autism and Developmental Disorders, 38(3), 507–515.

    Article  PubMed  Google Scholar 

  • Hu, M., Richard, J. E., Maliqueo, M., et al. (2015) Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring. Proceedings of the National Academy of Sciences USA, 112(46), 14348–1453.

    Article  Google Scholar 

  • Jacome, L. F., Barateli, K., Buitrago, D., Lema, F., Frankfurt, M., & Luine, V. N. (2016). Gonadal hormones rapidly enhance spatial memory and increase hippocampal spine density in male rats. Endocrinology, 157(4), 1357–1362.

    Article  PubMed  PubMed Central  Google Scholar 

  • Järvelä, I. Y., Pelkonen, S., Uimari, O., Mäkikallio, K., Puukka, K., Ruokonen, A., et al. (2014). Controlled ovarian hyperstimulation leads to high progesterone and estradiol levels during early pregnancy. Human Reproduction, 29(11), 2393–2401.

    Article  PubMed  Google Scholar 

  • Kim, Y. S., & Leventhal, B. L. (2015). Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biological Psychiatry, 77(1), 66–74.

    Article  PubMed  Google Scholar 

  • Knickmeyer, R., Baron-Cohen, S., Raggatt, P., & Taylor, K. (2005). Foetal testosterone, social relationships, and restricted interests in children. Journal of Child Psychology and Psychiatry, 46(2), 198–210.

    Article  PubMed  Google Scholar 

  • Knickmeyer, R., Baron-Cohen, S., Raggatt, P., Taylor, K., & Hackett, G. (2006). Fetal testosterone and empathy. Hormones and Behavior, 49(3), 282–292.

    Article  PubMed  Google Scholar 

  • Knickmeyer, R. C., Woolson, S., Hamer, R. M., Konneker, T., & Gilmore, J. H. (2011). 2D:4D ratios in the first 2 years of life: Stability and relation to testosterone exposure and sensitivity. Hormones and Behavior, 60(3), 256–263.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kondo, T., Zákány, J., Innis, J. W., & Duboule, D. (1997). Of fingers, toes and penises. Nature, 390(6655), 29.

    Article  PubMed  Google Scholar 

  • Krajmer, P., Spajdel, M., Kubranska, A., & Ostatnikova, D. (2011). 2D:4D finger ratio in Slovak autism spectrum population. Bratisl Lek Listy, 112(7), 377–379.

    PubMed  Google Scholar 

  • Kuijper, E. A., Twisk, J. W., Korsen, T., et al. (2015). Mid-pregnancy, perinatal, and neonatal reproductive endocrinology: A prospective cohort study in twins and singleton control subjects. Fertility and Sterility, 104(6), 1527–1534.e1-9.

    Article  PubMed  Google Scholar 

  • Lutchmaya, S., Baron-Cohen, S., & Raggatt, P. (2002a). Foetal testosterone and eye contact in 12 month old infants. Infant Behavior and Development, 25, 327–335.

    Article  Google Scholar 

  • Lutchmaya, S., Baron-Cohen, S., & Raggatt, P. (2002b). Foetal testosterone and vocabulary size in 18- and 24-month-old infants. Infant Behavior and Development, 24, 418–424.

    Article  Google Scholar 

  • Lutchmaya, S., Baron-Cohen, S., Raggatt, P., Knickmeyer, R., & Manning, J. T. (2004). 2nd to 4th digit ratios, fetal testosterone and estradiol. Early Human Development, 77(1–2), 23–28.

    Article  PubMed  Google Scholar 

  • Makieva, S., Saunders, P. T., & Norman, J. E. (2014). Androgens in pregnancy: Roles in parturition. Human Reproduction Update, 20(4), 542–559.

    Article  PubMed  PubMed Central  Google Scholar 

  • Manning, J. T., Baron-Cohen, S., Wheelwright, S., & Sanders, G. (2001). The 2nd to 4th digit ratio and autism. Developmental Medicine & Child Neurology, 43(3), 160–164.

    Article  Google Scholar 

  • Manning, J. T., & Bundred, P. E. (2000). The ratio of 2nd to 4th digit length: a new predictor of disease predisposition? Medical Hypotheses, 54(5), 855–857.

    Article  PubMed  Google Scholar 

  • Manning, J. T., Scutt, D., Wilson, J., & Lewis-Jones, D. I. (1998). The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen. Human Reproduction, 13(11), 3000–3004.

    Article  PubMed  Google Scholar 

  • Masuya, Y., Okamoto, Y., Inohara, K., Matsumura, Y., Fujioka, T., Wada, Y., & Kosaka, H. (2015). Sex-different abnormalities in the right second to fourth digit ratio in Japanese individuals with autism spectrum disorders. Molecular Autism, 6, 34. https://doi.org/10.1186/s13229-015-0028-x.

    Article  PubMed  PubMed Central  Google Scholar 

  • McIntyre MH (2006) The use of digit ratios as markers for perinatal androgen action. Reproductive Biology and Endocrinology, 4, 10.

    Article  PubMed  PubMed Central  Google Scholar 

  • Miles, J. H. (2011). Autism spectrum disorders—A genetics review. Genetic in Medicine, 13(4), 278–294.

    Article  Google Scholar 

  • Milne, E., White, S., Campbell, R., Swettenham, J., Hansen, P., & Ramus, F. (2006). Motion and form coherence detection in autistic spectrum disorder: Relationship to motor control and 2:4 digit ratio. Journal of Autism & Developmental Disorders, 36(2), 225–237.

    Article  Google Scholar 

  • Noipayak, P. (2009). The ratio of 2nd and 4th digit length in autistic children. Journal of the Medical Association of Thailand, 92(8), 1040–1045.

    PubMed  Google Scholar 

  • Ornoy, A., Weinstein-Fudim, L., & Ergaz, Z. (2016). Genetic syndromes, maternal diseases and antenatal factors associated with autism spectrum disorders (ASD). Frontiers in Neuroscience, 10, 316. https://doi.org/10.3389/fnins.2016.00316.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pointis, G., Latreille, M. T., Richard, M. O., D’Athis, P., & Cedard, L. (1987). Effect of natural progesterone treatment during pregnancy on fetal testosterone and sexual behavior of the male offspring in the mouse. Developmental Pharmacology and Therapeutics, 10(5), 385–392.

    Article  PubMed  Google Scholar 

  • Quinonez, S. C., & Innis, J. W. (2014). Human HOX gene disorders. Molecular Genetics and Metabolism, 111(1), 4–15.

    Article  PubMed  Google Scholar 

  • Ribeiro, E., Neave, N., Morals, R. N., & Manning, J. T. (2016) Direct versus indirect measurement of digit ratio (2DL:4D): A critical review of the literature and new data. Evolutionary Psychology, 1–8.

  • Rizwan, S., Manning, J. T., & Brabin, B. J. (2007). Maternal smoking during pregnancy and possible effects of in utero testosterone: evidence from the 2D:4D finger length ratio. Early Human Development, 83(2), 87–90.

    Article  PubMed  Google Scholar 

  • Saenz, J., & Alexander, G. M. (2013). Digit ratios (2D:4D), postnatal testosterone and eye contact in toddlers. Biological Psychology, 94(1), 106–108.

    Article  PubMed  Google Scholar 

  • Schendel, D. E., DiGuiseppi, C., Croen, L. A., et al. (2012). The study to explore early development (SEED): A multisite epidemiologic study of autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) network. Journal of Autism & Developmental Disorders, 42, 2121–2140.

    Article  Google Scholar 

  • Schug, T. T., Blawas, A. M., Gray, K., Heindel, J. J., & Lawler, C. P. (2015). Elucidating the links between endocrine disruptors and neurodevelopment. Endocrinology, 156(6), 1941–1951.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shapira, S. K., Tian, L. H., Aylsworth, A. S., et al. (2015). Development of a novel protocol for characterizing dysmorphology to enhance the phenotypic classification of autism spectrum disorder. Presented at the 2015 International Meeting for Autism Research, Atlanta, GA.

  • Sugie, Y., Sugie, H., Fukuda, T., & Osawa, J. (2010). Study of HOXD genes in autism particularly regarding the ratio of second to fourth digit length. Brain & Development, 32(5), 356–361.

    Article  Google Scholar 

  • Taylor, G. T., Manzella, F. M., Huffman, J., Cabrera, O. H., & Hoffman, J. (2017) Cognition in female rats after blocking conversion of androgens to estrogens. Hormones and Behavior. https://doi.org/10.1016/j.yhbeh.2017.02.011.

    PubMed  Google Scholar 

  • Teatero, M. L., & Netley, C. (2013). A critical review of the research on the extreme male brain theory and digit ratio (2D:4D). Journal of Autism & Developmental Disorders, 43(11), 2664–2676.

    Article  Google Scholar 

  • Thornton, J., Zehr, J. L., & Loose, M. D. (2009). Effects of prenatal androgens on rhesus monkeys: A model system to explore the organizational hypothesis in primates. Hormones and Behavior, 55(5), 633–645.

    Article  PubMed  PubMed Central  Google Scholar 

  • Toriola, A. T., Vääräsmäki, M., Lehtinen, M., et al. (2011). Determinants of maternal sex steroids during the first half of pregnancy. Obstetrics & Gynecology, 118(5), 1029–1036.

    Article  Google Scholar 

  • Trivers, R., Manning, J., & Jacobson, A. (2006). A longitudinal study of digit ratio (2D:4D) and other finger ratios in Jamaican children. Hormones and Behavior, 49(2), 150–156.

    Article  PubMed  Google Scholar 

  • van de Beek, C., Thijssen, J. H., Cohen-Kettenis, P. T., van Goozen, S. H., & Buitelaar, J. K. (2004). Relationships between sex hormones assessed in amniotic fluid, and maternal and umbilical cord serum: what is the best source of information to investigate the effects of fetal hormonal exposure? Hormones and Behavior, 46(5), 663–669.

    Article  PubMed  Google Scholar 

  • Velez, M. P., Arbuckle, T. E., Monnier, P., & Fraser, W. D. (2017). Is maternal periconceptional smoking associated with 2D:4D digit ratio in their children? Journal of Developmental Origins of Health and Disease, 8(5), 597–603.

    Article  PubMed  Google Scholar 

  • Ventura, T., Gomes, M. C., Pita, A., Neto, M. T., & Taylor, A. (2013). Digit ratio (2D:4D) in newborns: influences of prenatal testosterone and maternal environment. Early Human Development, 89(2), 107–112.

    Article  PubMed  Google Scholar 

  • Wiggins, L. D., Levy, S. E., Daniels, J., et al. (2015b). Autism spectrum disorder symptoms among children enrolled in the Study to Explore Early Development (SEED). Journal of Autism & Developmental Disorders, 45(10), 3183–3194.

    Article  Google Scholar 

  • Wiggins, L. D., Reynolds, A., Rice, C. E., et al. (2015a). Using standardized diagnostic instruments to classify children with autism in the study to explore early development. Journal of Autism & Developmental Disorders, 45(5), 1271–1280.

    Article  Google Scholar 

  • Zheng, Z., & Cohn, M. J. (2011). Developmental basis of sexually dimorphic digit ratios. Proceedings of the National Academy of Sciences of the United States of America, 108(39), 16289–16294.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by six cooperative agreements from the Centers for Disease Control and Prevention: Cooperative Agreement Number U10DD000180, Colorado Department of Public Health; Cooperative Agreement Number U10DD000181, Kaiser Foundation Research Institute (CA); Cooperative Agreement Number U10DD000182, University of Pennsylvania; Cooperative Agreement Number U10DD000183, Johns Hopkins University; Cooperative Agreement Number U10DD000184, University of North Carolina at Chapel Hill; and Cooperative Agreement Number U10DD000498, Michigan State University.

Author information

Authors and Affiliations

Authors

Contributions

LAS made substantial contributions to acquisition of data, study conception and design, analysis and interpretation of data, drafting the article, revising the article critically for important intellectual content, and gave final approval of the version to be published. LT made substantial contributions to study conception and design, analysis and interpretation of data, revising the article critically for important intellectual content, and gave final approval of the version to be published. ND, LC, JH-F, AA and SKS made substantial contributions to acquisition of data, study conception and design, interpretation of data, revising the article critically for important intellectual content, and gave final approval of the version to be published.

Corresponding author

Correspondence to Laura A. Schieve.

Ethics declarations

Conflict of interest

All authors report no conflicts of interest for this study.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all participants in this study.

Additional information

Disclaimer

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schieve, L.A., Tian, L., Dowling, N. et al. Associations Between the 2nd to 4th Digit Ratio and Autism Spectrum Disorder in Population-Based Samples of Boys and Girls: Findings from the Study to Explore Early Development. J Autism Dev Disord 48, 2379–2395 (2018). https://doi.org/10.1007/s10803-018-3495-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10803-018-3495-z

Keywords

Navigation