Handedness and the X chromosome: The role of androgen receptor CAG-repeat length

Abstract

Prenatal androgen exposure has been suggested to be one of the factors influencing handedness, making the androgen receptor gene (AR) a likely candidate gene for individual differences in handedness. Here, we examined the relationship between the length of the CAG-repeat in AR and different handedness phenotypes in a sample of healthy adults of both sexes (n = 1057). Since AR is located on the X chromosome, statistical analyses in women heterozygous for CAG-repeat lengths are complicated by X chromosome inactivation. We thus analyzed a sample of women that were homozygous for the CAG-repeat length (n = 77). Mixed-handedness in men was significantly associated with longer CAG-repeat blocks and women homozygous for longer CAG-repeats showed a tendency for stronger left-handedness. These results suggest that handedness in both sexes is associated with the AR CAG-repeat length, with longer repeats being related to a higher incidence of non-right-handedness. Since longer CAG-repeat blocks have been linked to less efficient AR function, these results implicate that differences in AR signaling in the developing brain might be one of the factors that determine individual differences in brain lateralization.

The molecular genetics of hand preference revisited

“…One study found association effects which were opposite in males and females for the CAG-repeat 33 . A different study found that right-handedness was associated with shorter CAG repeats in both sexes 34 , while another, which only included males, found that mixed-handedness was associated with longer CAG repeats 35 . - In a set of families affected by bipolar disorder, an association was found of a variant in COMT (catechol-O-methyltransferase) with relative hand skill, although this did not survive multiple testing correction 36 . COMT was studied because it was considered a candidate gene for bipolar disorder 37 . - A study of the genes SETDB1 (SET domain bifurcated 1) and SETDB2 (SET domain bifurcated 2) found that the single nucleotide polymorphism (SNP) rs4942830 in SETDB2 was significantly associated with hand preference as measured as a quantitative trait on the Edinburgh scale 38 (N=950 healthy people), although for the binary trait of left versus right-handedness, the p-value did not survive multiple testing correction 39 .…”

Whole exome sequencing for handedness in a large and highly consanguineous family

“…In general it is not clear that visceral and brain lateralization are closely linked developmentally, because people with situs inversus (visceral organs reversed on the left-right axis), and having the genetic condition Primary Ciliary Dyskinesia (PCD), did not show changes in rates of left-handedness or left-lateralized auditory language dominance in the largest studies of these issues to have been performed (McManus et al, 2004;Tanaka et al, 1999). Another genetic study of handedness focused on a repeat-length polymorphism at the androgen receptor locus on chromosome X, and found that the number of repeats was associated with handedness (Arning et al, 2015). However, each of these genetic findings requires further validation.…”

Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains

“…154 Table 2). Dopamine is very important in the functioning of the basal ganglia 39 , while steroid hormone 155 pathways have long been studied in relation to variability in brain anatomical laterality 40,41 , 156 handedness 42,43 , and language-related development 44,45 . The transcriptional asymmetries which we 157 observed in these developing subcortical structures may therefore play important roles in creating 158 broader functional lateralities for motor and language functions, also involving the cerebral cortex.…”