Abstract
The androgen receptor (AR), oestrogen receptor alpha (ESR1) and oestrogen receptor beta (ESR2) play essential roles in mediating the effect of sex hormones on sex differences in the brain. Using Voxel-based morphometry (VBM) and gene sizing in two independent samples (discovery n = 173, replication = 61), we determine the common and unique influences on brain sex differences in grey (GM) and white matter (WM) volume between repeat lengths (n) of microsatellite polymorphisms AR(CAG)n, ESR1(TA)n and ESR2(CA)n. In the hypothalamus, temporal lobes, anterior cingulate cortex, posterior insula and prefrontal cortex, we find increased GM volume with increasing AR(CAG)n across sexes, decreasing ESR1(TA)n across sexes and decreasing ESR2(CA)n in females. Uniquely, AR(CAG)n was positively associated with dorsolateral prefrontal and orbitofrontal GM volume and the anterior corona radiata, left superior fronto-occipital fasciculus, thalamus and internal capsule WM volume. ESR1(TA)n was negatively associated with the left superior corona radiata, left cingulum and left inferior longitudinal fasciculus WM volume uniquely. ESR2(CA)n was negatively associated with right fusiform and posterior cingulate cortex uniquely. We thus describe the neuroanatomical correlates of three microsatellite polymorphisms of steroid hormone receptors and their relationship to sex differences.
Highlights
Associations with each microsatellite polymorphism were analysed in the discovery cohort for androgen receptor (AR)(CAG)n (Tables 1 and 2), ESR1(TA)n (Tables 3 and 4) and ESR2(CA)n (Table 5) as well as in the replication cohort (Tables S5-7 in Supplementary Information). 3.1 Sex differences
Males had increased grey matter (GM) volume compared to females in regions situated in the temporal lobes, insula, hypothalamus and cerebellum
We found significant, replicable brain volume differences associated with three microsatellite polymorphisms of the sex hormone receptors that appeared mostly in regions of brain sex differences identified in prior research
Summary
Sex differences in brain structure are well-established across a range of studies. A UK Biobank study of 5,216 participants found multiple brain sex differences – including higher uncorrected volumes and surface areas in males and higher cortical thickness and white matter (WM) tract complexity in females. Specific regions, such as the right insula, were larger in males after correction, while areas like the superior parietal were larger in females (Ritchie et al, 2018). Burgeoning evidence suggests that many of these differences are attributable to specific biological factors
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