Abstract Details

Title The Genetic Architecture of the Human Hypothalamus and Its Involvement in Neuropsychiatric Behaviours and Disorders

Topic General Neurology

Presentation(s) S13 - General Neurology 1 (11:15 AM-11:27 AM)

Poster/Presentation
Number 001

Background

Despite the hypothalamus's crucial role in regulating neurological and metabolic functions, its genetic architecture remains poorly understood. Prior studies have been limited by a lack of automated segmentation tools for hypothalamic subunits, hindering genetic analyses.

Objective

The objective of this study was to uncover the genetic architecture of the human hypothalamus and its involvement in neuropsychiatric behaviours and disorders.

Design/Methods We conducted multivariate genome-wide association studies (GWAS) on hypothalamic imaging data from 32,956 individuals. An automated segmentation tool based on deep convolutional neural networks was used to acquire the largest imaging samples of the hypothalamus and its 6 subregions. A series of post-GWAS analyses were performed including functional annotation, gene mapping, gene set enrichment analysis, genetic correlations and overlap analyses as well as Mendelian randomization.

Results The study identified 23 significant genomic loci associated with the hypothalamus, with functional enrichment for genes involved in intracellular trafficking systems and metabolic processes of steroid-related compounds. Substantial genetic associations were observed between the hypothalamus and limbic system structures, as well as neuropsychiatric traits including chronotype, risky behaviour, cognition, satiety, and autonomic activity. Genetic overlaps between the hypothalamus and neuropsychiatric disorders were recognized for schizophrenia, Parkinson’s disease, stroke, etc. The strongest signal in the primary GWAS, the ADAMTS8 locus, was replicated in three independent datasets (N = 1,685-4,321) and was strengthened after meta-analysis. Mendelian randomization suggested a causal effect of lower ADAMTS8 expression on larger hypothalamic volumes.

Conclusions

The current study advances our understanding of complex structure-function relationships of the hypothalamus and provides insights into the molecular mechanisms that underlie hypothalamic formation.

Authors/Disclosures
Shi-Dong Chen, MD PRESENTER	Mr. Chen has nothing to disclose.
Bangsheng Wu	Bangsheng Wu has nothing to disclose.
Jin-Tai Yu, PhD	Prof. Yu has nothing to disclose.

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