MD-PhD Student (MSTP) University of Alabama at Birmingham (UAB) Heersink School of Medicine
Disclosure(s):
Rishi Devulapalli: No financial relationships to disclose
Introduction: The genetic and pathophysiologic basis of hydrocephalus, cerebrospinal fluid (CSF) volume, and measures of brain growth are largely unknown. The goal of our study was to identify the extent to which hydrocephalus, CSF volume, brain volume, and head circumference are genetically related.
Methods: We perform genome-wide and transcriptome-wide association studies (GWAS and TWAS, respectively) of CSF volume, total intracranial volume, and head circumference (normalized for age, sex, and genetic ancestry) from the UK Biobank and Early Growth Genetics Consortia. These data are analyzed against a TWAS of pediatric hydrocephalus (Hale et al. Cell Reports, 2021). Gene-set enrichment analysis (GSEA) was performed to identify shared functions of genes between hydrocephalus and neuroimaging phenotypes.
Results: GWAS of CSF volume identified rs2088882 within the locus containing GMNC (MAF= 0.38, p= 5.5x10-28), a gene that causes hydrocephalus through altering neural stem cell development, as the lead variant. TWAS of CSF volume identified 159 genes reaching experiment-wide significance (after Bonferroni correction for number of genes tested), where NUAK1 a serine/threonine protein-kinase that regulates DNA ploidy, is the most statistically significant gene (p= 2.68x10-13). We identify 5763, 810, and 420 genes associated with CSF volume, hydrocephalus, and shared between the two phenotypes (p < 0.05), respectively. GSEA of shared hydrocephalus and CSF volume associated genes (p < 0.05, n= 420) identifies the PI3K-Akt-mTOR signaling axis (FDR < 0.05), a pathway known to cause hydrocephalus and regulate cortical volume/development, as the most statistically significant pathway. Finally, we identify enrichment between shared hydrocephalus-CSF volume genes with total intracranial volume (p= 0.004) and birth weight (p= 0.02), but not with head circumference or gestational age.
Conclusion : The genetic basis of hydrocephalus, CSF volume, and brain volume are highly divergent. The extent to which genetic predetermination may play a role in response to CSF diversion to maximize neurodevelopmental potential should be explored longitudinally.
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