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. ### Competing Interest Statement SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK abello A/S, Eli Lilly and Co and managing board memberships in Proscion A/S and Intomics A/S. CML reports grants from Bayer AG and Novo Nordisk and has a partner who works at Vertex. ### Funding Statement HC was funded by the European Union under a Marie Skłodowska-Curie Postdoctoral Fellowship, Project 101064250, RMCmplxPheno. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or Horizon Europe. Neither the European Union nor the granting authority can be held responsible for them. CA, SMS and FJL recieve funding from Wellcome Trust 215573/Z/19/Z and 203139/Z/16/Z. SSV is supported by the Rhodes Scholarships, Clarendon Fund, and the Medical Sciences Doctoral Training Centre at the University of Oxford. NAB is supported by Wellcome Trust 218486/Z/19/Z. YC is supported by NIH P50 HD104224. SB is recieves funding from Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). C.M.L. is supported by the Li Ka Shing Foundation, NIHR Oxford Biomedical Research Centre, Oxford, NIH (1P50HD104224-01), Gates Foundation (INV-024200), and a Wellcome Trust Investigator Award (221782/Z/20/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank has approval from the North West Multi-centre Research Ethics Committee (http://www.ukbiobank.ac.uk/ethics/), which also covers the work in this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used within the manuscript is available upon application to the UK Biobank.