IIH, pseudotumor cerebri, is an increased intracranial pressure leading vision changes and headaches. Obesity is a major risk factor, but the causal relationship was not proven. Previously SNP array in 95 IIH patients (Kuehn et al. 2019) showed 3 loci without obesity relevance.

Using TwoSampleMR packages for GWAS data, effect estimates were calculated using different method including the maximum likelihood, MR Egger, and inverse variance-weighted (IVW). Instrumental variables from GWAS summary stats were selected by different thresholds of p-value, linkage disequilibrium R² (0.001), and clumping size. Exposure GWAS summary stats were derived from FinnGen, UK Biobank, and published data (e.g., GIANT consortium, NHGRI-EBI-GWAS catalog).

IIH GWAS summary stat included 16,380,402 SNPs in 102 European IIH cases (ICD-10 G93.2) was compared to 205,799 controls from FinnGen. Obesogenic traits showed a significant positive causal inference with IIH. They showed an odds ratio (OR) of 2.331 and 2.302 ([95%CI 1.057-5.143] and [1.054-5.027]) in maximum likelihood and IVW, respectively. Similar results were observed in other population datasets and consortia predominantly using the IVW: obesity and other hyperalimentation (OR 2.390 [1.119-5.104], p=0.024), childhood obesity (OR 2.558 [1.248-5.243], p=0.010), overweight (OR 2.577 [1.627-13.158], p=0.004), other obesity cohorts (OR 2.558 [1.247-5.244], p=0.036). Class III obesity (BMI >40) demonstrated a higher OR compared to class I obesity (BMI 30-35), with values of 2.311 [1.162-4.595] vs. 2.095 [1.052-4.170]) highlighting three notable variants: rs117280037, rs29939, and rs7973894. There was no evidence of horizontal pleiotropy nor heterogeneity supporting the robustness.

Our findings suggest the first evidence of genetic causal link between obesity and IIH, highlighting the importance of obesity control in managing IIH (Abbott et al. 2023, Neurology). Mechanistic studies on obesogenic genes and their interaction with other factors are warranted to understand the pathophysiology.