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

Abstract Background Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure without a known cause. IIH mainly affects overweight and reproductive-age women. Due to elevated intracranial pressure in IIH patients, papilledema (PAP), a disease caused by swelling of the optic disc, often co-occurs. Previous genome-wide association studies (GWAS) of common variants failed to find significant associations. Methods We applied genetic association protocols to a cohort of 173 patients diagnosed with IIH or PAP from the UK Biobank (UKB). The results were compared to the FinnGen data. We applied routine and coding GWAS (cGWAS) to a unified cohort of IIH/PAP. We also employed SKAT, which considers all variants within a given segment, and PWAS, which estimates the damage of variants to protein function and models a gene by aggregating its coding variants. Results The detection power of standard GWAS methods is restricted by cohort size and false discovery. To overcome these limitations, we considered gene-centric approaches for the unified group of IIH and PAP patients. Notably, the dominant comorbidity of IIH is PAP in the UKB and FinnGen populations. Seeking shared genes by GWAS for IIH and PAP identified VLDLR and SHANK2 genes in the UKB and FinnGen cohorts, respectively. By utilizing complementary gene-centric association protocols (coding GWAS, SKAT, and PWAS) for the unified IIH/PAP group, we identified 16 genes that were recognized by at least two methods, with FOXF1 and RGCC recognized by all three. Employing a functional enrichment scheme emphasized the significance of cilium, microtubule, and cytoskeletal functions. To gain insight into IIH etiology, we focused on the choroid plexus, a brain structure that produces and secretes the cerebrospinal fluid (CSF). Altogether, 7 of the 16 candidate genes are listed among the 281 genes with enhanced expression in the choroid plexus epithelium. Among them, MAPK15, DNAH5, and SLC28A3 are involved in ciliary microtubule dysregulation. Conclusions This study highlights the strength of integrative genetic association approaches with functional and clinical knowledge. By identifying potential genetic effects, we propose the biological and cellular relevance of the choroid plexus for IIH etiology and suggest candidate genes for further investigation.