Genetic Sex Interactions in Lipid Traits : A Comprehensive GWAS Analysis in South Korean Cohorts

다국어 초록 (Multilingual Abstract)

Sex differences in lipid metabolism are well recognized, yet the extent to which genetic factors contribute differently to lipid traits in men and women remains unclear. In this study, we asked whether specific genetic variants exert sex-dependent effects on four lipid traits—total cholesterol, HDL-C, triglycerides, and LDL-C—within a large Korean population cohort. To address this question, we performed genome-wide sex-by-genotype interaction analyses and sex-stratified association testing, followed by heritability estimation. We then explored the underlying functional role of the identified SNPs using eQTL and sex-differential expression data. Finally, these findings were replicated across multi-ancestry GWAS datasets. We identified 15 independent variants exhibiting significant genotype-by-sex interactions. Among these, eight variants showed opposite effect directions between sexes, while three displayed consistent directions but significantly different effect sizes. Stratified analyses revealed that rs13234269 and rs16940688 were significant exclusively in women, whereas rs4646776, rs76887905, and rs3782886 were specific to men. Especially, rs13234269 was positionally and functionally mapped to KLF14; this locus showed consistent sex-biased expression patterns, with significantly higher levels observed in female. We also calculated heritability to support these findings, but the differences between men and women were not significant. And functional annotation pointed to sex-dependent regulatory patterns, but interpretation remained constrained by the lack of sex-stratified eQTL information and ancestry-related mismatches in reference datasets. We conclude that sex-stratified and interaction-based analyses can reveal genetic associations that remain undetected in traditional sex-combined GWAS, underscoring the importance of incorporating sex-aware analytical strategies when investigating the genetic architecture of lipid traits.

목차 (Table of Contents)

• Ⅰ. Introduction 1
• 1.1 Background of lipid trait 1
• 1.2 Previous studies 1
• 1.3 Aims of the study 2
• Ⅱ. Method 3
• 2.1 Study cohorts 3
• 2.2 Biochemical measurements 3
• 2.3 Genotyping and Quality Control 4
• 2.4 Statistical analysis 4
• 2.5 Heritability and Functional annotation 5
• 2.6 Validation 5
• Ⅲ. Result 7
• 3.1 Demographics 7
• 3.2 Sex interaction analyses across lipid traits in GWAS 10
• 3.3 LDSC heritability 21
• 3.4 Comparison of expression data in eQTL mapped gene 22
• 3.5 Validation with Multi Ancestries GWAS results 29
• Ⅳ. Discussion 36
• V. Conclusion 40
• Reference 40
• Acknowledgments 47