2025 American Academy of Neurology Abstract Website

Hyun Yong Koh¹, Ryan Dhindsa², Seoyoung Park³, Woojae Myung⁴, Hong-Hee Won³, Daniel Calame¹, Michael Scheurer⁵, Timothy Lotze¹
¹Neurology, Baylor College of Medicine/Texas Children’s Hospital, ²Pathology, Baylor College of Medicine/Texas Children’s Hospital, ³Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea, ⁴Psychiatry, Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea, ⁵Pediatrics, Baylor College of Medicine/Texas Children’s Hospital

Objective:

To infer the genetic causality between obesity and IIH using genetic and phenotypic data from biobanks

Background:

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.

Design/Methods:

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).

Results:

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.

Conclusions:

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.