The genetics of idiopathic intracranial hypertension (IIH): Integration of population studies and clinical data

Abstract Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure without a known cause. It mainly affects overweight, reproductive-age women, and its genetic basis remains unknown. Previous GWAS failed to find significant associations. To address this, we analyzed a cohort of 173 IIH and papilledema (PAP) patients from the UK Biobank (UKB) using various genetic association methods. We activate a GWAS that covers only coding regions of genes for better interpretability. We also employed the complementary methods of SKAT and PWAS, which aggregate variants to determine gene-based association. We report on 10 overlapping genes by two methods, with FOXF1 and RGCC identified by all three methods. In a separate GWAS on a Finnish cohort, a rare variant in the LRRFIP1 gene was associated with IIH. Comparing findings from the Finnish, IIH, and PAP cohorts, we discovered the SHANK2 gene as a shared genetic factor. Genes related to the choroid plexus epithelium cluster (MAPK15, DCDC1, DNAH5, and SLC28A3) were found to be enriched, suggesting a role for microtubule cilia regulation in IIH etiology. Importantly, many GWAS-associated coding variants were predicted to be deleterious and rare in healthy populations. Comorbidities associated with IIH and PAP include pain, migraines, and psychological and mental disorders. This study highlights the strength of an integrative genetic approach, combining functional and clinical knowledge, to better understand IIH etiology. By identifying potential genetic factors and their biological relevance, this research provides insights into IIH's causes and paves the way for further investigation and potential therapeutic interventions.