Waller Cameron, Ho Ada, Batzler Anthony, Geske Jennifer, Karpyak Victor, Biernacka Joanna, Winham Stacey
Mayo Clinic.
Res Sq. 2024 Feb 28:rs.3.rs-3944066. doi: 10.21203/rs.3.rs-3944066/v1.
Alcohol consumption behaviors and alcohol use disorder risk and presentation differ by sex, and these complex traits are associated with blood concentrations of the steroid sex hormones, testosterone and estradiol, and their regulatory binding proteins, sex hormone binding globulin (SHBG) and albumin. Genetic variation is associated with alcohol consumption and alcohol use disorder, as well as levels of steroid sex hormones and their binding proteins.
To assess the contribution of genetic factors to previously described phenotypic associations between alcohol-use traits and sex-hormone levels, we estimated genetic correlations (r) using summary statistics from prior published, large sample size genome-wide association studies (GWAS) of alcohol consumption, alcohol dependence, testosterone, estradiol, SHBG, and albumin.
For alcohol consumption, we observed positive genetic correlation (i.e. genetic effects in the same direction) with total testosterone in males (r = 0.084, p = 0.007) and trends toward positive genetic correlation with bioavailable testosterone (r = 0.060, p = 0.084) and SHBG in males (r = 0.056, p = 0.086) and with albumin in a sex-combined cohort (r = 0.082, p = 0.015); however in females, we observed positive genetic correlation with SHBG (r = 0.089, p = 0.004) and a trend toward negative genetic correlation (i.e. genetic effects in opposite directions) with bioavailable testosterone (r = -0.064, p = 0.032). For alcohol dependence, we observed a trend toward negative genetic correlation with total testosterone in females (r = -0.106, p = 0.024) and positive genetic correlation with BMI-adjusted SHBG in males (r = 0.119, p = 0.017). Several of these genetic correlations differed between females and males and were not in the same direction as the corresponding phenotypic associations.
Findings suggest that shared genetic effects may contribute to positive associations of alcohol consumption with albumin in both sexes, as well as positive associations between alcohol consumption and bioavailable testosterone and between alcohol dependence and SHBG in males. However, relative contributions of heritable and environmental factors to associations between alcohol-use traits and sex-hormone levels may differ by sex, with genetic factors contributing more in males and environmental factors contributing more in females.
饮酒行为、酒精使用障碍风险及表现存在性别差异，这些复杂特征与甾体性激素睾酮和雌二醇及其调节性结合蛋白性激素结合球蛋白（SHBG）和白蛋白的血浓度相关。基因变异与饮酒量、酒精使用障碍以及甾体性激素及其结合蛋白水平有关。
为评估遗传因素对先前描述的饮酒相关性状与性激素水平之间表型关联的贡献，我们利用先前发表的、大样本量的全基因组关联研究（GWAS）中关于饮酒量、酒精依赖、睾酮、雌二醇、SHBG和白蛋白的汇总统计数据来估计遗传相关性（r）。
对于饮酒量，我们观察到男性总睾酮与之存在正遗传相关性（即遗传效应方向相同，r = 0.084，p = 0.007），与男性生物可利用睾酮存在正遗传相关性趋势（r = 0.060，p = 0.084）以及与男性SHBG存在正遗传相关性趋势（r = 0.056，p = 0.086），在性别合并队列中与白蛋白存在正遗传相关性（r = 0.082，p = 0.015）；然而在女性中，我们观察到与SHBG存在正遗传相关性（r = 0.089，p = 0.004），与生物可利用睾酮存在负遗传相关性趋势（即遗传效应方向相反，r = -0.064，p = 0.032）。对于酒精依赖，我们观察到女性总睾酮与之存在负遗传相关性趋势（r = -0.106，p = 0.024），男性BMI校正后的SHBG与之存在正遗传相关性（r = 0.119，p = 0.017）。这些遗传相关性中的一些在女性和男性之间存在差异，且与相应的表型关联方向不同。
研究结果表明，共享的遗传效应可能导致饮酒量与两性白蛋白之间的正关联，以及男性饮酒量与生物可利用睾酮之间、酒精依赖与SHBG之间的正关联。然而，遗传和环境因素对饮酒相关性状与性激素水平之间关联的相对贡献可能因性别而异，遗传因素在男性中贡献更大，环境因素在女性中贡献更大。
