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Background Little is known about remission, recovery, and other outcomes of alcohol use disorder (AUD) as defined by the DSM-5. Methods Data from a large representative sample of the United States was used to examine correlates of past-year AUD status among individuals with prior-to-past-year AUD: persistent AUD, symptomatic high-risk drinking, asymptomatic high-risk drinking, symptomatic low-risk drinking, asymptomatic low-risk drinking (nonabstinent recovery, NAR), and abstainer (abstinent recovery, AR). Multiple logistic regression analyses were conducted to compare: (i) AR and NAR with persistent AUD, (ii) AR with NAR, and (iii) asymptomatic and symptomatic high-risk drinking with AR and NAR. Results Among individuals with AUD prior to past year (n = 7,785), 34.2% were classified with persistent AUD, 8.8 and 1.6% were symptomatic high-risk and symptomatic low-risk drinkers, respectively, 21.5% were asymptomatic high-risk drinkers, 17.9% were asymptomatic low-risk drinkers, and 16.0% were abstainers. One-quarter of individuals with AUD prior to past year achieved AR or NAR without the benefit of treatment, while a much greater percentage of individuals achieving AR (43.2%) reported receiving treatment relative to those with NAR (12.3%). The number of lifetime AUD symptoms was greater among those achieving AR (among the treated) and lower among those achieving NAR relative to persistent AUD. The number of AUD symptoms was also greater among those achieving AR than NAR and lower among asymptomatic and symptomatic risk drinkers relative to those achieving AR and NAR. Consumption was greater among those achieving AR relative to those achieving NAR and greater among asymptomatic and symptomatic risk drinkers relative to AR and NAR. Odds of achieving AR or NAR relative to persistent AUD were generally lower among non-Hispanic Blacks and those with higher education, greater among women and married individuals, and lower among illicit drug users and individuals with histories of a personality disorder or mood/anxiety disorder. Conclusions There appears to be a substantial level of recovery from AUD. Information on specific factors associated with AUD outcomes can be useful in targeting appropriate treatment efforts.

BACKGROUND: The gene encoding Phosphatidylinositol-4-Phosphate 5-Kinase (PIP5K1C) has been recently implicated in pain regulation. Interestingly, a recent cross-tissue and cross-phenotypic epigenetic analysis identified the same gene in alcohol use disorder (AUD). Given the high comorbidity between AUD and chronic pain, we hypothesized that genetic variation in PIP5K1C might contribute to susceptibility to AUD. METHODS: We conducted a case-control association study of genetic variants in PIP5K1C. Association analyses of 16 common PIP5K1C single nucleotide polymorphisms (SNPs) were conducted in cases and controls of African (427 cases and 137 controls) and European Ancestry (488 cases and 324 controls) using standard methods. In addition, given the prominent role of the opioid system in pain signaling, we investigated the effects of acute alcohol exposure on PIP5K1C expression in humanized transgenic mice for the mu-opioid receptor that included the OPRM1 A118G polymorphism, a widely used mouse model to study analgesic response to opioids in pain. PIP5K1C expression was measured in the thalamus and basolateral amygdala (BLA) in mice after short-term administration (single 2g/kg dose) of alcohol or saline using immunohistochemistry and analyzed by two-way ANOVA. RESULTS: In the case-control association study using a NIAAA discovery sample, eight SNPs in PIP5K1C were significantly associated with AUD in the African ancestry group (p < 0.05 after correction; rs4807493, rs10405681, rs2074957, rs10432303, rs8109485, rs1476592, rs10419980, and rs4432372). However, a replication analysis using an independent sample (N= 3801) found no significant associations after correction for multiple testing. In the humanized transgenic mouse model with the OPRM1 polymorphism, PIP5K1C expression was significantly different between alcohol and saline-treated mice, regardless of genotype, in both the thalamus (p < 0.05) and BLA (p < 0.01). CONCLUSIONS: Our discovery sample shows that genetic variants in PIP5K1C are associated with AUD in the African ancestry group, and acute alcohol exposure leads to upregulation of PIP5K1C, potentially explaining one mechanism underlying the increased risk for chronic pain conditions in individuals with AUD.

In this paper, extensive simulations are performed to compare two statistical methods to analyze multiple correlated quantitative phenotypes: (1) approximate F-distributed tests of multivariate functional linear models (MFLM) and additive models of multivariate analysis of variance (MANOVA), and (2) Gene Association with Multiple Traits (GAMuT) for association testing of high-dimensional genotype data. It is shown that approximate F-distributed tests of MFLM and MANOVA have higher power and are more appropriate for major gene association analysis (i.e., scenarios in which some genetic variants have relatively large effects on the phenotypes); GAMuT has higher power and is more appropriate for analyzing polygenic effects (i.e., effects from a large number of genetic variants each of which contributes a small amount to the phenotypes). MFLM and MANOVA are very flexible and can be used to perform association analysis for: (i) rare variants, (ii) common variants, and (iii) a combination of rare and common variants. Although GAMuT was designed to analyze rare variants, it can be applied to analyze a combination of rare and common variants and it performs well when (1) the number of genetic variants is large and (2) each variant contributes a small amount to the phenotypes (i.e., polygenes). MFLM and MANOVA are fixed effect models which perform well for major gene association analysis. GAMuT can be viewed as an extension of sequence kernel association tests (SKAT). Both GAMuT and SKAT are more appropriate for analyzing polygenic effects and they perform well not only in the rare variant case, but also in the case of a combination of rare and common variants. Data analyses of European cohorts and the Trinity Students Study are presented to compare the performance of the two methods.

BACKGROUND: Recent studies have shown that alcohol use affects the regulation and expression of proprotein convertase subtilisin/kexin 9 (PCSK9). While a major role of PCSK9 in hepatic function and lipid regulation has been clearly established, other pleiotropic effects remain poorly understood. Existing research suggests a positive association between PCSK9 expression in the brain and psychopathology, with increased levels of PCSK9 in the cerebrospinal fluid (CSF) of individuals with dementia and epigenetic modifications of PCSK9 associated with Alcohol Use Disorder (AUD). In this study, we hypothesized that chronic alcohol use would increase PCSK9 expression in CSF. METHODS: PCSK9 levels in CSF were measured in individuals with AUD (n=42) admitted to an inpatient rehabilitation program and controls (n=25). CSF samples in AUD were assessed at two-time points, at day 5 and day 21 after admission. Furthermore, plasma samples were collected and measured from the individuals with AUD. RESULTS: PCSK9 in CSF was significantly increased in the AUD group at day 5 and day 21 compared to the controls (p < 0.0001). Plasma PCSK9 levels were correlated positively with CSF PCSK9 levels in AUD (p= 0.0493). CONCLUSIONS: Our data suggest that PCSK9 is elevated in the CSF of individuals with AUD, which may indicate a potential role of PCSK9 in AUD. Additional studies are necessary to further elucidate the functions of PCSK9 in the brain.