Disentangling the genetic overlap between ischemic stroke and obesity

Area of Science:

• Genetics and Epidemiology
• Neuroscience
• Public Health

Background:

• Obesity is a known risk factor for cerebrovascular diseases, including stroke.
• Previous observational studies suggest an increased incidence of stroke in individuals with obesity.
• The causal relationship and shared genetic underpinnings between obesity and ischemic stroke (IS) remain incompletely understood.

Purpose of the Study:

• To investigate the genetic correlation between body mass index (BMI) and ischemic stroke (IS).
• To determine the causal relationship between BMI and IS using Mendelian randomization.
• To identify shared genetic risk factors and potential functional genes implicated in both conditions.

Main Methods:

• Utilized linkage disequilibrium score regression and high-definition likelihood to assess genetic correlation.
• Employed bidirectional Mendelian randomization to infer causality between BMI and IS.
• Conducted cross-trait meta-analyses to identify shared single nucleotide polymorphisms (SNPs) and summary-data-based Mendelian randomization (SMR) for functional gene discovery.

Main Results:

• Demonstrated a significant positive genetic correlation, supporting a causal effect of BMI on IS.
• Identified 9 and 16 shared risk SNPs for IS and small vessel stroke (SVS), respectively.
• Found enrichment of SNP heritability in brain tissues and identified key shared genes (CHAF1A, CEP192, ULK4, CYP2D6, AS3MT, WARS2) involved in brain development and function.

Conclusions:

• Confirmed a significant genetic overlap and causal link between BMI and IS.
• Highlighted shared genetic risk SNPs and identified potential functional genes contributing to both conditions.
• The findings provide insights into the genetic interplay of obesity and IS, potentially guiding future therapeutic strategies.