The Genetics of Idiopathic Intracranial Hypertension (IIH): Integration of Population Studies and Clinical Data

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Israel Science Foundation (M.L) 2753/20 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committees/IRBs of the Hebrew University of Jerusalem approved the study. The data are based on consent obtained globally for all participants from the UK biobank I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The individual-level genotype data are available under the restriction of the UK Biobank (UKB) Data Analysis Platform. The UKB application ID 26664 (Linial lab).