Waller, Cameron

Abstract Objective Sex-specific differences impact vulnerability to alcohol effects, dependence (AD) and related phenotypes. Previous studies demonstrated that sex-related hormone and protein levels may contribute to those differences in sex-specific manner. However, previous studies were limited by sample size, the depths of phenotyping assessments and/or the number of hormones and proteins measured at the same time. Here, we investigated the association of the sex-related hormone (testosterone, estrogens, and progesterone) and protein (FSH, LH, SHBG, and albumin) levels with AD in males and females treated in community-based programs compared to age and sex-matched controls. We also investigated the associations of AD with the combined plasma sex-related hormone/protein “signatures” in the same groups of study subjects. Methods Sex-related hormone and protein levels were measured in plasma samples collected from 401 male and female subjects meeting DSM-IV-TR criteria for AD and 401 age and sex matched controls. Psychiatric Research Interview for Substance and Mental Disorder (PRISM) was used to capture DSM-IV diagnoses of substance use and other psychiatric disorders. All analyses were stratified by sex. Associations between each plasma sex-related hormone/protein level and AD was assessed with multivariable linear regression adjusted for age and BMI for males and age, BMI, and menopause status for females. Progesterone was defined as a continuous variable and a binary variable based on a lower laboratory detection limit of 0.1 ng/mL. We used principal component analysis to define hormone/protein signatures. Hormones and proteins with factor loadings =/> |0.4| were considered important drivers for the corresponding principal components (PCs). Resulting PCs were entered into a sex-stratified logistic regression model with adjustment of age and BMI to determine which PCs were associated with AD. Results Male AD subjects had higher estradiol and albumin levels (p <0.00625) as well as progesterone and LH levels (p <0.05) compared to controls. Progesterone was detected in a larger proportion of AD subjects than in the controls (62.6% vs. 47.7%; p = 0.017). In females, albumin levels were significantly higher (p <0.00385) while estrone and progesterone levels were lower (p <0.05) in AD subjects than the controls. Total testosterone (TT) levels were relatively higher in AD subjects but differences between groups were not significant (p >0.05). In males, the first PC (PC1) that accounted for the majority of data variance was significantly associated with AD (p=0.016) and was mostly driven by TT, estrone, estradiol and SHBG. PC3 (driven by albumin, progesterone and estradiol) and PC4 (driven by albumin and SHBG) were also associated with AD (p=0.007 and p<0.001, respectively). In females, PC1 (driven by estrone, estradiol, SHBG) was not significantly associated with AD. However, PC3 (driven by Albumin and progesterone), PC4 (driven by TT and Albumin) and PC5 (driven by progesterone and TT), were significantly associated with AD (p=0.009, p=0.001, p=0.004, respectively). Conclusion Our findings indicate that individual hormone/protein levels as well as hormone/protein combination signatures associated with AD are different in male and female alcoholics. Future studies should investigate physiological mechanisms reflected in hormone/protein signatures captured by PC analyses.

Abstract Background 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. Methods To assess the contribution of genetic factors to previously described phenotypic associations between alcohol-use traits and sex-hormone levels, we estimated genetic correlations (rg) using summary statistics from prior published, large sample size genome-wide association studies (GWAS) of alcohol consumption, alcohol dependence, testosterone, estradiol, SHBG, and albumin. Results For alcohol consumption, we observed positive genetic correlation (i.e. genetic effects in the same direction) with total testosterone in males (rg = 0.084, p = 0.007) and trends toward positive genetic correlation with bioavailable testosterone (rg = 0.060, p = 0.084) and SHBG in males (rg = 0.056, p = 0.086) and with albumin in a sex-combined cohort (rg = 0.082, p = 0.015); however in females, we observed positive genetic correlation with SHBG (rg = 0.089, p = 0.004) and a trend toward negative genetic correlation (i.e. genetic effects in opposite directions) with bioavailable testosterone (rg = -0.064, p = 0.032). For alcohol dependence, we observed a trend toward negative genetic correlation with total testosterone in females (rg = -0.106, p = 0.024) and positive genetic correlation with BMI-adjusted SHBG in males (rg = 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. Conclusions 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.