ANNOTATION OF GWAS VARIANTS TO IDENTIFY CANDIDATE MECHANISMS IN NORMAL PRESSURE HYDROCEPHALUS

Normal Pressure Hydrocephalus (NPH) is a chronic neurological syndrome in the elderly characterized by gait disturbance, cognitive impairment and bladder dysfunction. In NPH, cerebrospinal fluid (CSF) is building up to brain ventricles, although symptoms can be alleviated with shunt many patients still have long-term impairments indicating the need for better understanding of the molecular mechanisms underlying the disease. Our recent genome wide association study (GWAS) of NPH with FinnGen identified eight loci SLCO1A2, AMZ1/GNA12, MLLT10, CDCA2, C16orf95, PLEKHG1, ARHGEF12 and CSNK1E (Räsänen et al. 2024). To explore potential causal mechanisms at these loci, we performed comprehensive variant annotation to prioritize variants with predicted functional impact. Variants for annotation was chosen from NPH GWAS by using threshold p-value lower than 1e-6 which produced 857 variants. We used CADD, Regulome probability score, REVEL, SIFT, PolyPhen, Enformer, SpliceAI and eQTL’s of brain tissue. By these tools, we identified 117 candidate variants. Next, we aim to study their association to NPH phenotypes; with particular emphasis on brain structural measures such as ventricular volume. Linking functional predicted functional variants with phenotypes will help determine whether these candidates influence characteristic neuroanatomical features of NPH and will provide deeper insight into the biological processes driving disease pathogenesis. To conclude, we are using a variant annotation approach to identify protective or pathogenic variants for NPH and provide a foundation for follow up analyses and may help identify new molecular pathways relevant to disease development.