Elsevier

Evolution and Human Behavior

Volume 33, Issue 5, September 2012, Pages 557-561
Evolution and Human Behavior

Original Article
Re-examining the Manning hypothesis: androgen receptor polymorphism and the 2D:4D digit ratio

https://doi.org/10.1016/j.evolhumbehav.2012.02.003Get rights and content

Abstract

The ‘Manning hypothesis,’ the idea that small differences in the ratio of the lengths of the human second to fourth digits—the 2D:4D ratio—reflect differences in the level of fetal androgen exposure, has been highly influential in the biological and biobehavioral sciences. The ratio is widely used to investigate the involvement of fetal androgens in the differentiation of sexually dimorphic traits. The validity of such studies is based on the premise that individual differences in the size of the 2D:4D ratio mirror differences across individuals in developmental levels of androgen exposure in a dose-dependent manner. Despite its widespread adoption by researchers, clinical evidence has yet to confirm that individual gradation in the ratio denotes differences in testosterone action. Key support for the view that 2D:4D does, in fact, reflect fetal testosterone in a graded fashion is the finding, based on a single small-sample study, that the magnitude of 2D:4D covaries with a polymorphic repeat (CAG) sequence in exon 1 of the gene coding the androgen receptor, AR. In a larger independent sample, we reexamine this genetic association and fail to substantiate a correlation between AR CAG length and 2D:4D. Combined with other recent reports, these data question one of the fundamental pieces of evidence on which the Manning hypothesis rests and raise new issues regarding the extent to which 2D:4D is a valid reflection of differences in fetal testosterone action in normally developing individuals.

Introduction

The 2D:4D digit ratio—the ratio of the lengths of the second to fourth digits of the human hand—is a sexually dimorphic trait (Ecker, 1875). Although it varies considerably across individuals, men on average have a lower 2D:4D ratio than women. Interest in the ratio was triggered in 1998 when British researcher John Manning hypothesized that the sex difference in 2D:4D is determined by actions of testosterone in utero and that individual variation in the size of the ratio may be a proxy for individual differences in the level of fetal androgen exposure (Manning et al., 2003, Manning et al., 1998). Prenatal androgens are believed to masculinize the human central nervous system (Hines, 2011). Consequently, the prospect that 2D:4D represents a retrospective marker of the level of androgen exposure during the period when the brain is sexually differentiated has led to nearly 500 studies in the biosciences investigating links between the size of the ratio and variation in sex-related traits believed to be androgen-dependent ranging from autism, to fertility, to behavioral characteristics such as sexuality, risk-taking, or aggression (for review, see Manning, 2008).

The scientific integrity of these studies is based on the premise that individual variation in the ratio constitutes a valid marker of androgen action. The validity of 2D:4D, however, is contested. In favor of an androgen effect, the ratio is reduced (more male-typical) in patients with 21-hydroxylase deficiency who experience elevated androgens in utero (Brown et al., 2002, Ökten et al., 2002) and is female-typical in 46,XY patients with complete androgen insensitivity (Berenbaum, Bryk, Nowak, Quigley, & Moffat, 2009), in whom the androgen receptor (AR) fails to bind testosterone. These data confirm gross changes in the ratio in response to large deviations in androgen availability but do not confirm that small gradations in 2D:4D, visible among healthy persons of either sex, mirror fetal androgen exposure in a dose-dependent fashion. Variation in the ratio within each sex could potentially be an expression of multiple causative factors, not limited to or even largely reflective of androgen action (e.g., Zheng & Cohn, 2011). The view that individual variation in the ratio reflects androgen exposure in a graded, proportional manner is based largely on a single study that appeared in Evolution and Human Behavior. Manning et al. (2003) discovered that the size of the 2D:4D ratio covaries, across healthy males, with a repeat polymorphism in the gene that encodes the AR [number of polyglutamine (CAG) repeats in exon 1 of the AR gene], which is known to correlate inversely with the ability of the receptor to activate transcription of androgen-dependent target genes (Zitzmann, 2009). Manning reported that 2D:4D correlated positively with AR CAG length, supporting the view that individual differences in the ratio are a meaningful reflection of differences in the level of testosterone action.

Despite its theoretical importance, the Manning et al. (2003) result is based on only a single small sample of 50 men and has yet to be replicated. Recent work by Medland et al. (2010), using genomewide screening, and by Hurd, Vaillancourt, and Dinsdale (2011) has cast some doubt on the CAG association. In a study of aggressive behaviour, both 2D:4D and AR CAG length were measured by Hurd et al. (2011), but AR CAG length failed to show the anticipated correlation with 2D:4D (right hand: r=.006; left hand: r=−.12). Medland et al. (2010) failed to find any significant genetic association between 2D:4D and four different single nucleotide polymorphisms (SNPs) located within the AR gene, although CAG repeat expansion per se was not specifically measured.

Here, we report data in which AR CAG genotype was specifically quantified in a large sample of healthy young men in whom a dedicated measure of the 2D:4D ratio was taken. To evaluate the possibility that genetic variation in AR could lead to covariation in the production of testosterone via physiological feedback mechanisms (Crabbe et al., 2007)—which potentially could obscure any correlation—we also measured bioavailable testosterone in the same sample.

Section snippets

Participants

The current work was part of a larger investigation of associations between testosterone biomarkers, affect, and cognition. Participants were 152 physically healthy males recruited from the University of Western Ontario (M=18.72 years; S.D.=1.63; range=17–27 years). The sample was predominantly Caucasian; 10% of the sample was Asian. Participants were excluded if they reported an injury to their hands that could alter the growth of their second or fourth digits or if they had any known

Results

Consistent with previous reports (Fink et al., 2004, Hampson et al., 2008, Medland et al., 2010), the mean right hand 2D:4D for the males in our sample was M=.95, S.D.=.03, and the mean left hand 2D:4D was M=.95, S.D.=.03. Ethnic differences in 2D:4D have been reported in some subpopulations (Manning, Stewart, Bundred, & Trivers, 2004), but there was no evidence in our data that Asians and non-Asians systematically differed in either right or left hand ratios, F(1,149)=0.28, p =.595 (cf., Hurd

Discussion

The validity of the 2D:4D ratio as a gauge of testosterone action in utero has been the subject of fractious debate (Berenbaum et al., 2009, Breedlove, 2010). The idea that testosterone does underlie small individual differences in the ratio is supported primarily by Manning et al. (2003), who showed that the ratio covaried with AR CAG repeat length in a sample of 50 men, although a positive correlation was seen only for the right hand (r=.29), not the left (r=.005). Despite a much larger

Acknowledgments

We thank Christine Tenk for independent scoring of the digit ratios. This work was funded by the Natural Sciences and Engineering Research Council of Canada (E.H.). J.S. was supported by an Alexander Graham Bell Canada Graduate Scholarship. E.H. holds a chair from the Canadian Institutes of Health Research FRN: SOW97026.

References (30)

  • S.A. Berenbaum et al.

    Fingers as a marker of prenatal androgen exposure

    Endocrinology

    (2009)
  • S.M. Breedlove

    Organizational hypothesis: instances of the fingerpost

    Endocrinology

    (2010)
  • S.M. Breedlove et al.

    Sexual differentiation of the brain and behavior

  • P. Crabbe et al.

    Part of the interindividual variation in serum testosterone levels in healthy men reflects differences in androgen sensitivity and feedback set point: contribution of the androgen receptor polyglutamine tract polymorphism

    Journal of Clinical Endocrinology and Metabolism

    (2007)
  • A. Ecker

    Some remarks about a varying character in the hands of humans

    Archives of Anthropology (Braunschweig)

    (1875)
  • Cited by (0)

    View full text