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Lipid-lowering therapy with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition are effective strategies in reducing cardiovascular disease risk; however, concerns remain about potential long-term adverse neurocognitive effects.This genetics-based study aimed to evaluate the relationships of long-term PCSK9 inhibition and statin use on neurocognitive outcomes.We extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from predominantly European ancestry-based genome-wide association studies summary-level statistics of low-density lipoprotein cholesterol and performed drug-target Mendelian randomization, proxying the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using a range of outcomes to capture the complex facets of cognition and dementia.Using data from a combined sample of ∼740,000 participants, we observed a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive performance, memory performance, or cortical surface area. Conversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: -0.082; 95% CI: -0.16 to -0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = -0.18; 95% CI: -0.35 to -0.014; P = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer's disease progression or Lewy body dementia risk. Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference.Using a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.

Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value < 6.8 × 10−8) with the five leading probes located in SLC7A11 (p = 7.75 × 10−108), JDP2 (p = 1.44 × 10−56), GAS5 (p = 2.71 × 10−47), TRA2B (p = 3.54 × 10−42), and SLC43A1 (p = 1.18 × 10−40). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer’s disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p = 5.37 × 10−09). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p = 6.32 × 10−38 and p = 5.41 × 10−14). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N = 615) and showed strong hypomethylation in AUD (p −17). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p −4), increased liver function enzymes (GGT (p = 1.03 × 10−21), ALT (p = 1.29 × 10−6), and AST (p = 1.97 × 10−8)) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11 expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention.

Substance use disorders (SUDs) are moderately to highly heritable and are in part cross-transmitted genetically, as observed in twin and family studies. We performed exome-focused genotyping to examine the cross-transmission of four SUDs: alcohol use disorder (AUD, n = 4487); nicotine use disorder (NUD, n = 4394); cannabis use disorder (CUD, n = 954); and nonmedical prescription opioid use disorder (NMPOUD, n = 346) within a large nationally representative sample (n = 36,309), the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III). All diagnoses were based on in-person structured psychiatric interview (AUDADIS-5). SUD cases were compared alone and together to 3959 "super controls" who had neither a SUD nor a psychiatric disorder using an exome-focused array assaying 363,496 SNPs, yielding a representative view of within-disorder and cross-disorder genetic influences on SUDs. The 29 top susceptibility genes for one or more SUDs overlapped highly with genes previously implicated by GWAS of SUD. Polygenic scores (PGS) were computed within the European ancestry (EA) component of the sample (n = 12,505) using summary statistics from each of four clinically distinct SUDs compared to the 3959 "super controls" but then used for two distinctly different purposes: to predict SUD severity (mild, moderate, or severe) and to predict each of the other 3 SUDs. Our findings based on PGS highlight shared and unshared genetic contributions to the pathogenesis of SUDs, confirming the strong cross-inheritance of AUD and NUD as well as the distinctiveness of inheritance of opioid use disorder.

BACKGROUND: Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood.METHODS: We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation-based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795).RESULTS: Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation-based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts.CONCLUSIONS: A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.

Alcohol withdrawal syndrome (AWS) is a serious medical condition of high variability in alcohol use disorder (AUD) after drinking cessation. Identification of clinical biomarkers capable of detecting severe AWS is needed. While alcohol consumption and withdrawal are linked with lipid profile dysregulation, the relationship between lipid levels (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) and AWS is unknown. Therefore, this study investigated whether HDL-C, LDL-C, and triglycerides conferred risk for moderate-to-severe AWS symptoms in treatment-seeking individuals (n = 732) admitted to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcohol treatment program. Lipid levels were measured upon admission, and the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) assessed AWS severity for generating a three-level AWS typology (none-to-mild, moderate, and severe). Multivariable multinomial logistic regression examined whether lipid levels were associated with risk for moderate-to-severe AWS. We found significant predictive relationships between AWS and HDL-C, LDL-C, and triglycerides. While extremely high HDL-C (≥100 mg/dL) conferred the highest odds for moderate (4.405, 95% CI, 2.572–7.546, p < 0.001) and severe AWS (5.494, 95% CI, 3.541–8.523, p < 0.001), the lowest odds ratios for moderate AWS (0.493, 95% CI, 0.248–0.981, p = 0.044) and severe AWS (0.303, 95% CI, 0.223–0.411, p < 0.001) were associated with high LDL-C (≥160 mg/dL). The present study demonstrates that altered lipid levels, measured upon admission for inpatient AUD treatment, may help to predict which individuals are at risk for medically relevant moderate-to-severe AWS. This suggests that further research into the role of lipid biomarkers in AWS may be beneficial for identifying biologically determined risk profiles in AUD.

This qualitative study explores how a group of preservice teachers, all of whom had been well prepared to become primary-grade teachers, made a transition into infant/toddler group care settings. T...

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

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.

To investigate the potential role of alcohol use disorder (AUD) in aging processes, we employed Levine’s epigenetic clock (DNAm PhenoAge) to estimate DNA methylation age in 331 individuals with AUD and 201 healthy controls (HC). We evaluated the effects of heavy, chronic alcohol consumption on epigenetic age acceleration (EAA) using clinical biomarkers, including liver function test enzymes (LFTs) and clinical measures. To characterize potential underlying genetic variation contributing to EAA in AUD, we performed genome-wide association studies (GWAS) on EAA, including pathway analyses. We followed up on relevant top findings with in silico expression quantitative trait loci (eQTL) analyses for biological function using the BRAINEAC database. There was a 2.22-year age acceleration in AUD compared to controls after adjusting for gender and blood cell composition (p = 1.85 × 10−5). This association remained significant after adjusting for race, body mass index, and smoking status (1.38 years, p = 0.02). Secondary analyses showed more pronounced EAA in individuals with more severe AUD-associated phenotypes, including elevated gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT), and higher number of heavy drinking days (all ps

Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value6.8 × 10

Alcohol use disorder (AUD) is a major contributor to morbidity and mortality worldwide. Although there is a heritable component, the etiology of AUD is complex and can involve environmental exposures like trauma and can be associated with many different patterns of alcohol consumption. Epigenetic modifications, which can mediate the influence of genetic variants and environmental variables on gene expression, have emerged as an important area of AUD research. Over the past decade, the number of studies investigating AUD and DNA methylation, a form of epigenetic modification, has grown rapidly. Yet we are still far from understanding how DNA methylation contributes to or reflects aspects of AUD. In this paper, we reviewed studies of DNA methylation and AUD and discussed how the field has evolved. We found that global DNA and candidate DNA methylation studies did not produce replicable results. To assess whether findings of epigenome‐wide association studies (EWAS) were replicated, we aggregated significant findings across studies and identified 184 genes and 15 gene ontological pathways that were differentially methylated in at least two studies and four genes and three gene ontological pathways that were differentially methylated in three studies. These genes and pathways repeatedly found enrichment of immune processes, which is in line with recent developments suggesting that the immune system may be altered in AUD. Finally, we assess the current limitations of studies of DNA methylation and AUD and make recommendations on how to design future studies to resolve outstanding questions., The number of studies investigating DNA methylation patterns in individuals with alcohol use disorder (AUD) has grown steadily over the past decade. Here, we review research on AUD and DNA methylation and identify CpG sites that have been most frequently replicated.

Biological ageing estimators derived from DNA methylation (DNAm) data are heritable and correlate with morbidity and mortality. Leveraging DNAm and SNP data from >41,000 individuals, we identify 137 genome-wide significant loci (113 novel) from meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We report strong genetic correlations with longevity and lifestyle factors such as smoking, education, and obesity. Significant associations are observed in polygenic risk score analysis and to a lesser extent in Mendelian randomization analyses. This study illuminates the genetic architecture underlying epigenetic ageing and its shared genetic contributions with lifestyle factors and longevity.

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.

AIMS: Previous genetic association studies have shown that variation in the GATA4 gene encoding the GATA binding protein 4, a binding protein that binds to the ANA sequence GATA, increase susceptibility for alcohol use disorder (AUD). In this study, we aimed to replicate those findings in an independent sample and analyze their association with anxiety. METHODS: Overall, 1044 individuals with AUD [534 European American (EA), 510 African Americans (AA)] and 645 controls [413 EA, 232 AA] were genotyped using 34 markers. Genotype and allele frequencies were compared between cases and controls using chi-square analysis. Other phenotype data were analyzed for possible associations with GATA4 single-nucleotide polymorphisms (SNPs) in individuals with AUD. RESULTS: Rs6601604 was nominally significantly associated with AUD in EA, and 3 SNPs (rs6990313, rs11250159 and rs17153694) showed trend-level significance (P < 0.10) in AA. However, none of the SNPs were significant after correcting for multiple testing. Haplotype analysis of the 34 SNPs did not find a significant association between haplotype blocks and AUD diagnosis after correcting for multiple testing. From the phenotype analysis, anxiety was associated with GATA4 SNP rs10112596 among the AA group with AUD after a correction for multiple testing. CONCLUSIONS: Although previous studies have shown a relationship between variants of the GATA4 gene and a diagnosis of AUD, we did not replicate these findings in our sample. Additional studies of variation in this gene are needed to elucidate whether polymorphisms of the GATA4 gene are associated with AUD and other alcohol-related phenotypes. SHORT SUMMARY: GATA4 variants were not associated with AUD in either the European ancestry or African ancestry groups after correcting for multiple comparisons. Rs10112596 demonstrated a significant relationship with an anxiety measure among the African ancestry group with AUD.

Pathway-based analysis has the ability to detect subtle changes in response variables that could be missed when using gene-based analysis. Since genes interact with other covariates such as environmental or clinical variables, so do pathways, which are sets of genes that serve particular cellular or physiological functions. However, since pathways are sets of genes and since environmental or clinical variables do not have parametric relationships with response variables, it is difficult to model unknown interaction terms between high-dimensional variables and low-dimensional variables as environmental or clinical variables. In this paper, we propose a semiparametric interaction model for two unknown functions to evaluate the interaction between a pathway and environmental or clinical variable: for the pathway, we use an unknown high-dimensional function, and for environmental or clinical variable, we use an unknown low-dimensional function. We model the environmental or clinical variable nonparametrically via a natural cubic spline. We model both the pathway effect and the interaction between the pathway and environmental or clinical effect nonparametrically via a kernel machine. Since both interactions among genes within the same pathway and the interaction between the pathway and the environmental or clinical variables are complex, we allow for the possibility that a pathway is interacting with environmental or clinical variables and the genes within the same pathway are interacting with each other. We illustrate our approach using simulated data and genetic pathway data for type II diabetes. Supplementary materials accompanying this paper appear online.

We conducted the first genome-wide association study (GWAS) in Generalized Anxiety Disorder (GAD) to identify potential predictors of venlafaxine XR treatment outcome. Ninety-eight European Americans (EA) patients participated in a venlafaxine XR clinical trial for GAD, with Hamilton Anxiety Scale (HAM-A) response/remission at 24 weeks as the primary outcome measure. All participants were genotyped with the Illumina PsychChip, and 266,820 common single nucleotide polymorphisms (SNPs) were analyzed. Although no SNPs reached genome-wide significance, 8 SNPs were marginally associated with treatment response/remission and HAM-A reduction at week 12 and 24 (p < 0.00001). Several identified genes may indicate markers crossing neuropsychiatric diagnostic categories.

The inclusive education of children with disabilities is considered best practice, yet many early childhood educators feel unprepared to deliver appropriate instruction for children with disabilities and often require supports to successfully meet the children’s unique needs. Young children experiencing autism spectrum disorder are being diagnosed at a young age and they are commonly receiving their education within inclusive early childhood settings. This article presents two methods to meet the needs of children with autism spectrum disorder. First, early childhood educators can provide interventions tailored to the children’s learning needs. Second, educators can adapt the environment, materials, activity, instruction, and assistance they provide so that each child is appropriately supported, while still being encouraged to succeed as independently as possible. This article summarizes research-based interventions and adaptations that early childhood educators can implement within inclusive settings to meet the diverse needs of young children with autism spectrum disorder and presents a case study to describe how these practices can support young children with autism spectrum disorder within inclusive settings.

The purpose of this paper is to advance the discourse on parental involvement drawing from Butlerian notion of strategic provisionality. In developing a new approach to understanding cultural diffe...

Purpose The purpose of this study was to present current nationally representative data on the prevalences, sociodemographic correlates and risk of DSM-5 substance use disorders and other psychiatric disorders among sexual minorities (SMs) relative to heterosexuals, and among SMs by gender. Methods Data were derived from the 2012–2013 National Epidemiologic Survey on Alcohol and Related Conditions-III. Results In the general noninstitutionalized population, 1.5%, 1.3% and 0.5% of individuals self-identified as gay/lesbian, bisexual and not sure sexual orientations. Men were more likely to report gay/lesbian orientation than women (1.8% vs. 1.2%). Women were more likely than men to report bisexual (1.8% vs. 0.8%) and not sure (0.6% vs. 0.4%) sexual orientations. Sociodemographic characteristics varied across sexual orientation and gender. Relative to heterosexuals, disparities in substance use and psychiatric disorders were found across sexual orientations, especially among bisexual women. Greater rates of specific psychiatric disorders were also demonstrated by women reporting bisexual and not sure orientations relative to lesbian women, with fewer differences in rates of psychopathology among SM men. Conclusions Despite growing acceptance of SMs and SM rights over the past decade, substantial mental health disparities exist among these subgroups of the U.S. noninstitutionalized population, especially among bisexual women. More research is needed to understand these mental health disparities, while considering nuances of multiple intersecting minority identities and unique contextual factors. Findings underscore the importance of advancing future population-based research that includes detailed information on the health and well-being of SMs in the United States.

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: Cardiomyopathy is a major cause of death in patients with systemic transthyretin amyloidosis. Long term effect of therapy designed to inhibit hepatic production of the amyloid precursor...

Alcohol use disorder (AUD) is a chronic debilitating disorder with limited treatment options and poorly defined pathophysiology. There are substantial genetic and epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted the largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-phenotypic approach with the goal of identifying novel epigenetic targets relevant to AUD. Results show that a network of differentially methylated regions in glucocorticoid signaling and inflammation-related genes were associated with alcohol use behaviors. A top probe consistently associated across all cohorts was located in the long non-coding RNA growth arrest specific five gene (GAS5) (p −24). GAS5 has been implicated in regulating transcriptional activity of the glucocorticoid receptor and has multiple functions related to apoptosis, immune function and various cancers. Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network-related probes were associated with stress phenotypes. Postmortem brain analyses documented increased GAS5 expression in the amygdala of individuals with AUD. Our data suggest that alcohol use is associated with differential methylation in the glucocorticoid system that might influence stress and inflammatory reactivity and subsequently risk for AUD.

Observational studies suggest that lower educational attainment (EA) may be associated with risky alcohol use behaviors; however, these findings may be biased by confounding and reverse causality. We performed two-sample Mendelian randomization (MR) using summary statistics from recent genome-wide association studies (GWAS) with >780,000 participants to assess the causal effects of EA on alcohol use behaviors and alcohol dependence (AD). Fifty-three independent genome-wide significant SNPs previously associated with EA were tested for association with alcohol use behaviors. We show that while genetic instruments associated with increased EA are not associated with total amount of weekly drinks, they are associated with reduced frequency of binge drinking ≥6 drinks (ßIVW = −0.198, 95% CI, −0.297 to –0.099, PIVW = 9.14 × 10−5), reduced total drinks consumed per drinking day (ßIVW = −0.207, 95% CI, −0.293 to –0.120, PIVW = 2.87 × 10−6), as well as lower weekly distilled spirits intake (ßIVW = −0.148, 95% CI, −0.188 to –0.107, PIVW = 6.24 × 10−13). Conversely, genetic instruments for increased EA were associated with increased alcohol intake frequency (ßIVW = 0.331, 95% CI, 0.267–0.396, PIVW = 4.62 × 10−24), and increased weekly white wine (ßIVW = 0.199, 95% CI, 0.159–0.238, PIVW = 7.96 × 10−23) and red wine intake (ßIVW = 0.204, 95% CI, 0.161–0.248, PIVW = 6.67 × 10−20). Genetic instruments associated with increased EA reduced AD risk: an additional 3.61 years schooling reduced the risk by ~50% (ORIVW = 0.508, 95% CI, 0.315–0.819, PIVW = 5.52 × 10−3). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference. Our findings suggest EA may have important effects on alcohol consumption patterns and may provide potential mechanisms explaining reported associations between EA and adverse health outcomes.

AimHigh-intensity binge drinking (HIBD), defined as two or more times the gender-specific binge threshold, is rapidly increasing in the USA; however, the underlying contributing factors are poorly understood. This study investigated the relationship of adverse childhood experiences (ACEs) and HIBD.MethodsTwo independent, cross-sectional samples were analysed: (a) past 12-month drinkers in the National Epidemiological Survey on Alcohol and Related Conditions-III (NESARC-III; n = 25,552) and (b) the National Institute on Alcohol Abuse and Alcoholism (NIAAA) clinical sample (n = 1303). Multinomial logistic regressions were utilized to estimate adjusted odds ratios (AORs) of ACEs on HIBD. Mediation analysis was performed to examine the relationship between the past 12-month psychiatric disorders, ACEs, and HIBD.ResultsIn the NESARC-III sample, prevalence of ACEs increased across all binge levels with the highest prevalence in extreme HIBD; ACEs were associated with higher odds for HIBD (level II, odds ratio (OR) = 1.2–1.4; P = 0.03–0.001; level III, OR = 1.3–1.9; P ConclusionACEs were associated with significantly increased odds of HIBD and the relationship may be mediated by psychiatric disorders.

Key Points Question What changes in circulating lipid and liver function enzyme levels are associated with high-intensity binge drinking? Findings In this cross-sectional study of 1519 participants, high-intensity binge drinking was associated with increased cholesterol, triglyceride, and liver function enzyme levels. Meaning Lipid and liver function enzyme levels demonstrate dose-dependent increases with high-intensity binge drinking, indicating potential adverse health outcomes may be associated with such drinking behavior., This cohort study examines the associations of high-intensity binge drinking with changes in levels of serum lipids and liver function enzymes., Importance The prevalence of high-intensity binge drinking (HIBD), defined as consuming 2 or more times the binge threshold defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), is rapidly increasing in the United States. While the relationship between alcohol consumption and lipid and liver function enzyme (LFT) biomarkers has been previously examined, the associations of HIBD with those biomarkers remain unknown. Objective To examine associations of HIBD with lipid and LFT levels in a cross-sectional sample enriched with participants who engage in HIBD. Design, Setting, and Participants Cross-sectional study using data from the NIAAA clinical sample collected from March 3, 2005, to August 21, 2017, with participants recruited for either the NIAAA screening protocols or inpatient alcohol treatment program. For this study, participants were stratified by self-reported alcohol consumption into 4 sex-specific binge levels: nonbinge and 1, 2, and 3 or more times the binge threshold (levels I, II, and III). Multivariable analyses examined the odds of clinically high levels of lipids and LFTs across binge levels. Analyses were performed from December 3, 2018, to January 30, 2019. Main Outcomes and Measures Serum levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase. Results A total of 2065 participants underwent protocol screening; 1519 with data available on alcohol consumption, body mass index, lipid levels, and LFT levels were included in the final analyses. Mean (SD) age was 39.7 (12.1) years; mean (SD) body mass index was 26.6 (5.1); 978 (64.4%) were male; 718 (47.3%) were white; and 578 (31.1%) consumed alcohol at the nonbinge level, 321 (21.2%) at level I, 239 (15.7%) at level II, and 318 (25.1%) at level III. High-intensity binge drinking was associated with 2- to 8-fold increased odds for clinically high levels of HDL-C, total cholesterol, triglycerides, and all LFTs (eg, for HDL-C: level III odds ratio [OR], 8.65; 95% CI, 4.75-15.77 and for γ-glutamyltransferase: level III OR, 8.21; 95% CI, 5.90-11.43). Increased HIBD frequency (days consuming at levels II and III) was associated with increased odds for clinically high levels of HDL-C, total cholesterol, and all LFTs (per unit increase in days consuming at the respective binge level) (eg, for HDL-C: level II OR, 1.025; 95% CI, 1.014-1.036 and level III OR, 1.033; 95% CI, 1.019-1.047 and for γ-glutamyltransferase: level II OR, 1.028; 95% CI, 1.019-1.037 and level III OR, 1.033; 95% CI, 1.019-1.047). Conclusions and Relevance High-impact binge drinking was significantly associated with increased odds for clinically high levels of lipids and LFTs. Given that HIBD is increasingly common among US adults, targeted interventions aimed at reducing HIBD may have important health benefits.

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.

Aims Differences in DNA methylation of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression and predict brain functions in healthy individuals. This study investigated the association between SLC6A4 promoter methylation and threat-related amygdala activation in individuals with alcohol dependence (AD). Methods Methylation of the SLC6A4 promoter region was assessed using peripheral blood DNA from 45 individuals with AD and 45 healthy controls (HCs). All participants completed an emotional face matching task in a 3-T magnetic resonance imaging (MRI) scanner. Results Results did not reveal any association between SLC6A4 promoter methylation variation and threat-related amygdala activation in HCs or individuals with AD. Furthermore, methylation in the promoter region of SLC6A4 did not significantly differ between the groups. Conclusions Our results do not replicate a previous finding that increased methylation in the promoter region of SLC6A4 is associated with threat-related amygdala activation in healthy individuals and further show that there is no such association in individuals with AD. Given that the number of imaging epigenetics studies on SLC6A4 is very limited to date, these inconsistent results indicate that future research is needed to clarify its association with amygdala reactivity in both healthy and clinical populations.

Objective The authors present 12-month and lifetime prevalence, correlates, psychiatric comorbidity, and treatment of nonmedical prescription opioid use (NMPOU) and DSM-5 NMPOU disorder (NMPOUD). Methods Data were derived from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) (N = 36,309). Results Prevalences of 12-month and lifetime NMPOU were 4.1% and 11.3%, exceeding rates in the 2001-2002 NESARC (1.8%, 4.7%). Twelve-month and lifetime rates of DSM-5 NMPOUD were 0.9% and 2.1%. NESARC-III DSM-IV NMPOUD rates (0.8%, 2.9%) were greater than those observed in the 2001-2002 NESARC (0.4% and 1.4%). Rates of NMPOU were greater among men, but no sex differential was observed for NMPOUD. Prevalences of NMPOU and NMPOUD were generally greater among 18- to 64-year-old individuals, whites, and Native Americans, and individuals with lower socioeconomic status. Associations were observed between 12-month and lifetime NMPOU and NMPOUD and other drug use disorders, posttraumatic stress disorder, and borderline, schizotypal, and antisocial personality disorders; persistent depression and major depressive disorder (for NMPOU); and bipolar I disorder (for NMPOUD). Only 5.5% and 17.7% of individuals with 12-month NMPOU and NMPOUD were ever treated. Conclusions NMPOU and NMPOUD have considerably increased over the past decade, are associated with a broad array of risk factors and comorbidities, and largely go untreated in the United States. More information on the determinants, characteristics, and outcomes of NMPOU and NMPOUD is needed to support evidence-based interventions and prevention.

To present nationally representative information on the prevalence, correlates, psychiatric comorbidity, and treatment of DSM-5 nicotine use disorder (NUD) and the public health burden of US cigarette consumption among adults with NUD and other psychiatric disorders.Using data from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (N = 36,309), we conducted weighted cross-tabulations and multivariate logistic regression analyses to estimate prevalences and examine comorbidity of NUD.Prevalences of 12-month and lifetime DSM-5 NUD were 20.0% and 27.9%, respectively. Nicotine use disorder was more frequent among men, non-Hispanic whites, younger individuals, the previously married, those with less education and lower incomes, and those residing in rural areas. Adjusting for sociodemographic characteristics and additional psychiatric comorbidity, 12-month NUD and lifetime NUD were significantly associated with other substance use and antisocial personality disorders (odds ratios [ORs] = 1.5-5.1, 12-month; 1.5-5.6, lifetime). Twelve-month severe NUD was generally associated with major depressive, bipolar I, bipolar II, panic, generalized anxiety, posttraumatic stress, and schizotypal, borderline, and antisocial personality disorders (ORs = 1.3-2.5). Individuals with current NUD and at least 1 psychiatric disorder comprised 11.1% of US adults but smoked 53.6% of total cigarettes consumed. Treatment was utilized by 20.3% of respondents with 12-month and 18.8% with lifetime NUD.Findings underscore the need to address nicotine use in clinical settings. Recognition of psychiatrically vulnerable subpopulations may inform etiologic research, prevention, and treatment of NUD.

To present current, nationally representative US findings on the past-year and lifetime prevalences, sociodemographic correlates, psychiatric comorbidity, associated disability, and treatment of DSM-5 posttraumatic stress disorder (PTSD). Face-to-face interviews with 36,309 adults in the 2012–2013 National Epidemiologic Survey on Alcohol and Related Conditions-III. PTSD, alcohol and drug use disorders, and selected mood, anxiety, and personality disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Past-year and lifetime prevalences were 4.7 and 6.1 %, higher for female, white, Native American, younger, and previously married respondents, those with

Alcohol dependence (AD) frequently co-occurs with major depressive disorder (MDD). While this comorbidity is associated with an increase in disease burden, worse treatment outcomes, and greater economic costs, the underlying neurobiology remains poorly understood. A recent large-scale GWAS of MDD has identified a locus in the TMEM161B-MEF2C region (rs10514299) as a novel risk variant; however, the biological relevance of this variant has not yet been studied. Given previous reports of disrupted reward processing in both AD and MDD, we hypothesized that rs10514299 would be associated with differences in striatal BOLD responses during reward/loss anticipation in AD. DNA samples from 45 recently detoxified patients with AD and 45 healthy controls (HC) were genotyped for rs10514299. Participants performed the Monetary Incentive Delay task in a 3-Tesla MRI scanner. Effects of rs10514299 on striatal activation during anticipation of high/low reward/loss were investigated. Furthermore, we examined associations between rs10514299 and lifetime AD diagnosis in two independent clinical samples [NIAAA: n = 1858 (1123 cases, 735 controls); SAGE: n = 3838 (1848 cases, 1990 controls)], as well as its association with depression severity in a subsample of individuals with a lifetime AD diagnosis (n = 953). Patients carrying the T allele showed significantly greater putamen activation during anticipation of high reward (p = 0.014), low reward (at trend-level; p = 0.081), high loss (p = 0.024), and low loss (p = 0.046) compared to HCs. Association analyses in the NIAAA sample showed a trend-level relationship between rs10514299 and a lifetime AD diagnosis in the European American subgroup (odds ratio = 0.82, p = 0.09). This finding was not replicated in the SAGE sample. In the NIAAA sample, the T allele was significantly associated with greater depression symptom severity in individuals with a lifetime AD diagnosis (β = 1.25, p = 0.02); this association was driven by the African American ancestry subgroup (β = 2.11, p = 0.008). We show for the first time that the previously identified MDD risk variant rs10514299 in TMEM161B-MEF2C predicts neuronal correlates of reward processing in an AD phenotype, possibly explaining part of the shared pathophysiology and comorbidity between the disorders.

To present nationally representative data on changes in the prevalences of 12-month cocaine use, cocaine use disorder (CocUD) and 12-month CocUD among 12-month cocaine users between 2001 and 2002 and 2012–2013. Data were derived from the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and the 2012–2013 NESARC-III. Between 2001 and 2002 and 2012–2013, prevalences of 12-month cocaine use and DSM-IV CocUD significantly increased and 12-month CocUD among 12-month users significantly decreased. Increases in risk of cocaine use were seen across nearly all sociodemographic subgroups while increases in CocUD were observed among women, those in the oldest age group, Whites, individuals with the lowest incomes and highest education, and those residing in urban areas. Prevalence of CocUD among users significantly declined overall and among men, individuals aged 30–44 years old, the never-married, respondents with incomes between $20,000 and $34,000, and those residing in the Midwest. Increases in coca cultivation in Colombia in recent years together with increases in the purity of cocaine entering the U.S. portend more significant increases in the rates of cocaine use and CocUD in the U.S. along with increases in cocaine-related morbidity and mortality. The results of this study support the continued monitoring of cocaine use and CocUD in the U.S., especially in view of the narrowing of the gender gap and shifts in race-ethnic, age and socioeconomic differentials seen between 2001 and 2002 and 2012–2013.

The purpose of this study was to assess the procedural validity of the substance disorder modules of the lay-administered Alcohol Use Disorder and Associated Disabilities Interview Schedule, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Version (AUDADIS-5) through clinician re-appraisal re-interviews.The study employed a test-retest design among 712 respondents from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III). A clinician-administered, semi-structured interview, the Psychiatric Research Interview for Substance and Mental Disorders, DSM-5 version (PRISM-5) was used as the re-appraisal. Kappa coeffients indicated concordance of the AUDADIS-5 and PRISM-5 for DSM-5 substance use disorder diagnoses, while intraclass correlation coefficients (ICC) indicated concordance on dimensional scales indicating the DSM-5 criteria count for each disorder.With few exceptions, concordance of the AUDADIS-5 and the PRISM-5 for DSM-5 diagnoses of substance use disorders ranged from fair to good (κ=0.40-0.72). Concordance on dimensional scales was excellent (ICC≥0.75) for the majority of DSM-5 SUD diagnoses, and fair to good (ICC=0.43-0.72) for most of the rest.As indicated by concordance with a semi-structured clinician-administered re-appraisal, the procedural validity of the AUDADIS-5 DSM-5 substance use disorder diagnoses found in this study indicates that these AUDADIS-5 diagnoses are useful tools in epidemiologic studies. The considerably stronger concordance of the AUDADIS-5 and PRISM-5 dimensional DSM-5 SUD measures supports a current movement to place more emphasis on dimensional measures of psychopathology, and suggests that such measures may be more informative than binary diagnoses for research, and possibly for clinical purposes as well.

Importance Lack of current and comprehensive trend data derived from a uniform, reliable, and valid source on alcohol use, high-risk drinking, andDSM-IValcohol use disorder (AUD) represents a major gap in public health information. Objective To present nationally representative data on changes in the prevalences of 12-month alcohol use, 12-month high-risk drinking, 12-monthDSM-IVAUD, 12-monthDSM-IVAUD among 12-month alcohol users, and 12-monthDSM-IVAUD among 12-month high-risk drinkers between 2001-2002 and 2012-2013. Design, Setting, and Participants The study data were derived from face-to-face interviews conducted in 2 nationally representative surveys of US adults: the National Epidemiologic Survey on Alcohol and Related Conditions, with data collected from April 2001 to June 2002, and the National Epidemiologic Survey on Alcohol and Related Conditions III, with data collected from April 2012 to June 2013. Data were analyzed in November and December 2016. Main Outcomes and Measures Twelve-month alcohol use, high-risk drinking, andDSM-IVAUD. Results The study sample included 43 093 participants in the National Epidemiologic Survey on Alcohol and Related Conditions and 36 309 participants in the National Epidemiologic Survey on Alcohol and Related Conditions III. Between 2001-2002 and 2012-2013, 12-month alcohol use, high-risk drinking, andDSM-IVAUD increased by 11.2%, 29.9%, and 49.4%, respectively, with alcohol use increasing from 65.4% (95% CI, 64.3%-66.6%) to 72.7% (95% CI, 71.4%-73.9%), high-risk drinking increasing from 9.7% (95% CI, 9.3%-10.2%) to 12.6% (95% CI, 12.0%-13.2%), andDSM-IVAUD increasing from 8.5% (95% CI, 8.0%-8.9%) to 12.7% (95% CI, 12.1%-13.3%). With few exceptions, increases in alcohol use, high-risk drinking, andDSM-IVAUD between 2001-2002 and 2012-2013 were also statistically significant across sociodemographic subgroups. Increases in all of these outcomes were greatest among women, older adults, racial/ethnic minorities, and individuals with lower educational level and family income. Increases were also seen for the total sample and most sociodemographic subgroups for the prevalences of 12-monthDSM-IVAUD among 12-month alcohol users from 12.9% (95% CI, 12.3%-17.5%) to 17.5% (95% CI, 16.7%-18.3%) and 12-monthDSM-IVAUD among 12-month high-risk drinkers from 46.5% (95% CI, 44.3%-48.7%) to 54.5% (95% CI, 52.7%-56.4%). Conclusions and Relevance Increases in alcohol use, high-risk drinking, andDSM-IVAUD in the US population and among subgroups, especially women, older adults, racial/ethnic minorities, and the socioeconomically disadvantaged, constitute a public health crisis. Taken together, these findings portend increases in many chronic comorbidities in which alcohol use has a substantial role.

OBJECTIVE To present current, nationally representative US findings on prevalence, correlates, psychiatric comorbidity, disability, and treatment of DSM-5 antisocial personality disorder (ASPD) and adulthood antisocial behavioral syndrome without conduct disorder before 15 years of age (AABS). METHOD Face-to-face interviews were conducted with respondents (N = 36,309) in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III. DSM-5 alcohol, nicotine, and specific drug use disorders and selected mood, anxiety, trauma-related, eating, and personality disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. RESULTS Prevalences of ASPD and AABS were 4.3% and 20.3%, respectively, and were highest among male, white, Native American, younger, and unmarried respondents, those with high school or less education, lower incomes, and Western residence. Both antisocial syndromes were significantly associated with 12-month and lifetime substance use, dysthymia/persistent depressive, bipolar I, posttraumatic stress, and borderline and schizotypal personality disorders (odds ratios [ORs] = 1.2-7.0). ASPD was additionally associated with 12-month agoraphobia and lifetime generalized anxiety disorder (ORs = 1.3-1.6); AABS, with 12-month and lifetime major depressive and 12-month generalized anxiety disorders (ORs = 1.2-1.3). Both were associated with significant disability (P < .001 to .01). Most antisocial survey respondents were untreated. CONCLUSIONS One in 4 US adults exhibits syndromal antisocial behavior, with similar sociodemographic and psychiatric correlates and disability regardless of whether onset occurred before 15 years of age, illustrating the clinical and public health significance of both ASPD and AABS. In addition to laying groundwork for estimates of social and economic costs, and further etiologic and nosologic research, these findings highlight the urgency of effectively preventing and treating antisocial syndromes, including investigation of whether treatment for comorbidity hastens symptomatic remission and improves quality-of-life outcomes.