The Phenotypic Correlates and Genetic Basis of the Central Neuroendocrine System

Abstract

The hypothalamus is considered the body’s principal center for maintaining homeostasis and orchestrating the secretion of multiple hormones. The pineal gland closely interacts with the hypothalamus and forms an essential component of circadian regulation via melatonin secretion. Assessing their structural characteristics and phenotypic correlates across the lifespan could therefore provide novel insights into the neurobiological basis of age-associated dysregulation of a range of bodily functions. However, comprehensive population-based studies were lacking. <br/> Using cross-sectional data from the Rhineland Study and the UK Biobank Study, two large-scale population-based cohort studies, we conducted the projects to address this gap. In both cohorts, volumes of hypothalamic structures and pineal gland were obtained from 3T structural MRI through an automatic parcellation (FastSurfer-HypVINN). Standardized cognitive domain scores were derived from extensive neuropsychological test batteries. Genotype data underwent rigorous quality control and were imputed using high-quality reference panels. <br/> We employed multivariable linear regression to assess associations of volumes of hypothalamic structures and pineal gland with age, sex as well as cognitive performance. We observed that, in older individuals, volumes of total hypothalamus, anterior hypothalamus, posterior hypothalamus and mammillary bodies were smaller, while those of medial hypothalamus and tuberal region were larger. Volumes of all hypothalamic structures were larger in men compared to women. In both sexes, larger volumes of total hypothalamus, anterior hypothalamus, posterior hypothalamus and mammillary bodies were associated with better domain-specific cognitive performance, whereas larger medial hypothalamus and tuberal region were associated with worse domain-specific cognitive performance. Additionally, we found that the pineal gland volume was larger in women and exhibited an accelerated decrease with age. Additionally, pineal gland volume was associated with larger volumes of total brain, grey matter, hippocampus, cerebellum and hypothalamus, as well as higher mean cortical thickness. Importantly, after adjustment for generalized brain atrophy, larger pineal gland volume was associated with better global cognitive performance as well as with a faster processing speed in both datasets. We further conducted the first GWAS of pineal gland volume, demonstrating 19% heritability and identifying 34 genome-wide significant loci, with highly concordant results between the two independent cohorts. Gene mapping and functional annotation highlighted multiple genes and pathways involved in numerous traits including sleep, metabolism, neurodevelopment and neurodegeneration. Mendelian randomization indicated a causal relationship between pineal gland volume and daytime napping. <br/> In summary, this thesis investigated age- and sex-related changes in volumes of hypothalamic structures (including its subregions) and pineal gland across adult lifespan, as well as their association with cognitive function. Additionally, the genetic architecture of pineal gland volume was investigated. The findings described in this thesis advance our understanding of the neurobiological mechanisms underlying age-associated disruptions in bodily homeostatic functions, particularly in the context of age-related neurodegenerative disorders.