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

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.