Genome-wide analysis identifies 66 variants underlying anatomical variation in human neuroendocrine structures and reveals links to testosterone

The hypothalamus, pituitary gland and olfactory bulbs are neuro-anatomical structures key to the regulation of the endocrine system. Variation in their anatomy can affect the function of the reproductive system. To investigate this relationship, we extracted four largely unexplored phenotypes from 34,834 individuals within UK Biobank by quantifying the volume of the hypothalamus, pituitary gland and olfactory bulbs using multi-modal magnetic resonance imaging. Genome-wide association studies of these phenotypes identified 66 independent common genetic associations with endocrine-related neurological volumes (P < 5 × 10⁻⁸), five of which had a prior association to testosterone levels, representing enrichment of testosterone-associated SNPs over random chance (P-value = 9.89 × 10⁻¹²). Exome-wide rare variant burden analysis identified STAB1 as being significantly associated with hypothalamus volume (P = 3.78 × 10⁻⁷), with known associations to brain iron levels. Common variants associated with hypothalamic grey matter volume were also found to be associated with iron metabolism, in which testosterone plays a key role. These results provide initial evidence of common and rare genetic effects on both anatomical variation in neuroendocrine structures and their function in hormone production and regulation. Variants associated with pituitary gland volume were enriched for gene expression specific to theca cells, responsible for testosterone production in ovaries, suggesting shared underlying genetic variation affecting both neurological and gonadal endocrine tissues. Cell-type expression enrichment analysis across hypothalamic cell types identified tanycytes to be associated (P = 1.69 × 10⁻³) with olfactory bulb volume associated genetic variants, a cell type involved in release of gonadotropin-releasing hormone into the bloodstream. Voxel-wise analysis highlighted associations between the variants associated with pituitary gland volume and regions of the brain involved in the drainage of hormones into the bloodstream. Together, our results suggest a shared role of genetics impacting both the anatomy and function of neuroendocrine structures within the reproductive system in their production and release of reproductive hormones.