Waller, T. Cameron

AbstractBackground and AimsSex‐related hormones and proteins may underlie sex differences in alcohol use disorder characteristics and consequences. Previous reports suggest steroid sex hormones may influence alcohol consumption behaviors while proteins that regulate their circulation levels are rarely investigated. Following up on our earlier study of individual sex‐related hormones' associations with alcohol dependence (AD), this study measured the associations between the combinations of sex‐related hormones and proteins and AD in a larger sample.DesignSex‐stratified case‐control comparison and clustering of plasma sex‐related hormone and protein levels, plus a genome‐wide association study on the AD‐associated hormone and protein combinations.SettingAddiction treatment programs in the United States.ParticipantsFour hundred treatment‐seeking recently abstained AD patients (median = 24.5 days) and 388 age‐and‐sex‐matched controls from a community biobank (male:female ≈ 2:1).MeasurementsPlasma levels of total testosterone, estrone (E1), estradiol (E2), follicle‐stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG) and albumin.FindingsIn males, we found higher E2 [β = 0.13, Punadjusted < 0.001, false discovery rate (FDR) = 0.005], progesterone (β = 0.01, Punadjusted = 0.025, FDR = 0.054), LH (β = 0.12, Punadjusted = 0.017, FDR = 0.044) and albumin (β = 0.09, Punadjusted < 0.001, FDR = 0.005) in AD patients than controls; in females, we observed lower E1 (β = −0.24, Punadjusted = 0.024, FDR = 0.113) and progesterone (β = −1.86, Punadjusted = 0.026, FDR = 0.113) and higher albumin (β = 0.18, Punadjusted < 0.001, FDR = 0.001) in AD patients than controls. Three principal components (PCs), reflecting hormone signatures, were statistically significantly associated with AD in each sex: PC1 (TT, E2 and SHBG; β = −0.15, P = 0.016), PC3 (E1, progesterone and albumin; β = 0.28, P = 0.007) and PC4 (SHBG and albumin; β = 0.34, P = 0.001) in males; PC3 (progesterone and albumin; β = −0.38, P = 0.009), PC4 (TT and albumin; β = −0.49, P = 0.001) and PC5 (TT and progesterone; β = 0.54, P = 0.004) in females. Statistically significant SNP × group associations were found in females between PC4 and polymorphisms in RP51004I9.1 (top SNP: rs6082693; P = 5.41E‐12) and in males between PC3 and a genomic locus that contained SLC35E4, DUSP18 and OSBP2 (top SNP: rs13053277; P = 1.77E‐07).ConclusionsThree sex‐related hormone and protein signatures appear to be associated with alcohol dependence in each sex. Peripheral levels of sex‐related hormones and proteins, as well as their combinations, could be altered in people with alcohol dependence who have abstained for a few weeks compared with controls, and such differences may be sex‐specific.

ABSTRACTBackgroundInsomnia and substance use disorders (SUD) are common comorbidities of bipolar disorder (BD). Genome‐wide association studies (GWAS) have uncovered shared genetic contributions to insomnia and BD as well as SUDs and BD. Electronic health record (EHR) derived phenotypes (phecodes) and questionnaire data were used to examine the relationship between insomnia genetic liability and SUDs in BD.Methods40,839 participants from the Mayo Clinic Bipolar Disorder Biobank (BD Biobank; n = 774) and Mayo Clinic Biobank (n = 485 BD cases, n = 39,580 controls) were included in the analyses of diagnosis (phecode) outcomes (insomnia, SUD, alcohol use disorder [AUD] and tobacco use disorder [TUD]). Analyses of specific SUD outcomes obtained through the BD Biobank questionnaire included 1789 cases and considered BD subtype. Logistic regression was used to test for associations between insomnia polygenic risk scores (PRS) and insomnia and SUD outcomes in BD cases and controls.ResultsInsomnia PRS was associated with having an insomnia diagnosis (phecode) in the EHR in controls (OR = 1.19, p = 9.64e‐33) but not in BD cases (OR = 1, p = 0.95). Associations between insomnia PRS and SUD diagnoses were significant in BD cases and controls, with the association being stronger in BD cases (interaction p = 0.024). In the BD Biobank data, the insomnia PRS was associated with increased odds of AUD (OR = 1.19, p = 4.26e‐04), TUD (OR = 1.21, p = 1.25e‐05) and cannabis use disorder (OR = 1.16, p = 4.19e‐03).ConclusionThe effect of genetic predisposition to insomnia on SUD risk may be stronger in BD cases than in controls, which could have clinical care implications for individuals with BD and comorbid SUD.