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Abstract 10446: Sex-Specific Genetic Loci Shared Between Sex Hormone Biomarkers and Coronary Heart Disease Are Associated with Sex- and Tissue-Specific Gene Expression


 Introduction:
 Sex differences in coronary heart disease (CHD) have been well-recognized, but the underlying mechanisms are poorly understood. To examine sex differences in the shared genetics between sex hormone biomarkers and CHD, we have previously performed a sex-stratified genome-wide association study for testosterone (T), sex-hormone binding globulin (SHBG), and CHD using data from the UK Biobank (187,888 men and 221,014 women). We then performed sex-stratified genome-wide cross-traits meta-analyses and identified 13 loci coregulating T or SHBG and CHD, with the coregulation effects specific to one sex (
 P
 meta
 <5х10
 -8
 in one sex and
 P
 meta
 ≥1х10
 -5
 in the other).
 
 
 Hypothesis:
 The identified sex-specific coregulatory loci are associated with gene expression in a sex-dependent manner, which could help elucidate sex-specific biological functions of shared genetics between sex hormones and CHD.
 
 
 Methods:
 Based on gene expression data in 49 different human tissues for >900 post-mortem donors of both sexes (the Genotype-Tissue Expression project; V8 release), we estimated genetic effects on sex- and tissue-specific expression for the 13 identified sex-specific coregulatory loci. False discovery rate (FDR) was used to account for multiple testing.
 
 
 Results:
 We observed 149 significant locus-gene associations in men (FDR
 men
 <0.05) and 72 in women (FDR
 women
 <0.05) in various tissues. Moreover, 19 locus-gene pairs showed sex-differed associations in various tissues (FDR for sex-locus interactions <0.05), 13 of which were in brain tissues (5 in cortex, 3 in cerebellum, 3 in hypothalamus, and 2 in basal ganglia); all of these loci were associated with expressions of genes whose transcription start sites are located at over 1 million bases away or on a different chromosome. We also observed 11 locus-gene pairs in male-specific tissues (9 in testis and 2 in prostate) and another 9 pairs in female-specific tissues (5 in vagina, 3 in ovary, and 1 in uterus).
 
 
 Conclusions:
 Sex-specific genetic loci shared between T or SHBG and CHD are associated with gene expressions in various tissues, predominantly in brain tissues, and such associations significantly differ by sex. Our findings may help advance the understanding of mechanisms underlying sex differences in CHD.
