Sex-specific autosomal genetic effects across 26 human complex traits

Area of Science:

• Genetics
• Human Biology
• Population Health

Background:

• Previous research indicates sex-specific genetic architectures for numerous human traits.
• However, the comparative strength of genetic effects between males and females remains largely unexplored for most traits, with exceptions like waist-to-hip ratio (WHR) and waist circumference (WC).
• Understanding these sex-based genetic differences is crucial for personalized medicine and comprehending trait variability.

Purpose of the Study:

• To comprehensively investigate sexual heterogeneity in autosomal genetic effects across a wide range of health-related traits.
• To identify specific traits exhibiting significant gene-by-sex interactions (G x S).
• To explore potential biological mechanisms, such as hormonal influences, underlying observed genetic sex differences.

Main Methods:

• Analysis of genetic data from approximately 18,000 individuals from the Taiwan Biobank.
• Systematic investigation of gene-by-sex interactions (G x S) for 26 traits including cardiovascular, diabetes, kidney, liver, anthropometric, and blood markers.
• Statistical analysis to detect significant interactions with a stringent p-value threshold adjusted for multiple testing.

Main Results:

• Significant gene-by-sex interactions (G x S) were detected in 18 out of 26 investigated traits.
• The strongest G x S evidence was observed for waist-to-hip ratio (WHR) and waist circumference (WC).
• Autosomal genetic effects were found to be weaker in women compared to men for low-density lipoprotein cholesterol (LDL-C), uric acid (UA), fasting glucose, and glycated hemoglobin. This effect was particularly pronounced in individuals under 50 years old, suggesting a role for estrogen.

Conclusions:

• Sex is a significant factor influencing the genetic architecture of many common health traits.
• Genetic effects for several metabolic and anthropometric traits are demonstrably weaker in women than in men.
• Sex can serve as a valuable surrogate for complex, unquantified environmental and hormonal factors that modulate gene expression and trait manifestation.