Alcohol Consumption Questionnaire: Scale development in a sample of Mexican American young adults and association with ADH7.

BACKGROUND: To understand why some individuals who develop alcohol use disorders (AUD) first begin to drink heavily, a number of scales have been developed that index aspects of alcohol craving and restraint from drinking. We developed a new measure called the Alcohol Consumption Questionnaire (ACQ), based in part on items modified from scales used to index binge eating because there are data to suggest that binge eating and binge drinking may share common antecedents. We present an initial validity study using data from a sample of Mexican Americans. METHODS: Data were from 699 Mexican American young adults in San Diego County, CA. A subsample (n=60) had short-term test-retest data. Factor analysis and reliability assessment guided item reduction. Item response theory (IRT) analyses quantified item severity and identified questions with differential item functioning (DIF). Logistic regression assessed associations of mean scale scores with AUD, adjusting for key demographics, alcohol expectancies and subjective response to alcohol. We also examined associations with a protective genetic variant downstream from the alcohol dehydrogenase 7 gene (ADH7). RESULTS: The scale was reduced from 20 to 14 questions, which can be summarized by a single overall score (Cronbach's alpha=0.896) or by two sub-scores (Consumption: 12 items, Cronbach's alpha=0.896; Enjoyment: 2 items, Cronbach's alpha=0.780). Test-retest reliability was very high (0.80-0.98) in this sample. The overall ACQ score and each subdomain score were strongly associated with AUD (ORs= 5.95 mild; 11.41 moderate; 48.56 severe) and family history of AUD. Respondents with the protective genetic variant had significantly lower overall ACQ scores (p<.001). CONCLUSION: The ACQ is a novel measure of alcohol consumption with strong relationships with both the AUD phenotype and ADH7 gene variants in a sample of Mexican American young adults.

Social zeitgeber and sleep loss as risk factors for suicide in American Indian adolescents.

American Indians / Alaska Natives (AI/AN) bear a high burden of suicide, the reasons for which are not completely understood, and rates can vary by tribal group and location. This article aims to identify circumstances reported by a community group of American Indian adolescent participants to be associated with their depression and/or suicide. American Indian adolescents (n = 360) were recruited from contiguous reservations and were assessed with a semi-structured diagnostic interview. Twenty percent of the adolescents reported suicidal thoughts (ideation, plans), an additional 8% reported a history of suicide attempts, and three deaths due to suicide were reported. Suicidal behaviors and major depressive disorder (MDD) co-occurred and were more common among female adolescents. The distressing events that adolescents most often reported were: death in the family, family disruption, peer relationship problems, and school problems. All of these events were significantly associated with suicidal behaviors, however those with suicidal acts were more likely to report death in the family. Those with MDD but no suicidal behaviors were more likely to report disruptions in the family. Disruptions in falling asleep were also associated with suicidal behaviors and having experienced a death in the family. Disruptions in important relationships, particularly through death or divorce, may be interpreted as a loss or disruption in "social zeitgebers" that may in turn disturb biological rhythms, such as sleep, thus potentially increase the risk for MDD and/or suicide. Prevention programs aimed at ameliorating the impact of disruptions in important relationships may potentially reduce suicidal behaviors in AI/AN adolescents.

Genetic factors associated with suicidal behaviors and alcohol use disorders in an American Indian population.

American Indians (AI) demonstrate the highest rates of both suicidal behaviors (SB) and alcohol use disorders (AUD) among all ethnic groups in the US. Rates of suicide and AUD vary substantially between tribal groups and across different geographical regions, underscoring a need to delineate more specific risk and resilience factors. Using data from over 740 AI living within eight contiguous reservations, we assessed genetic risk factors for SB by investigating: (1) possible genetic overlap with AUD, and (2) impacts of rare and low-frequency genomic variants. Suicidal behaviors included lifetime history of suicidal thoughts and acts, including verified suicide deaths, scored using a ranking variable for the SB phenotype (range 0-4). We identified five loci significantly associated with SB and AUD, two of which are intergenic and three intronic on genes AACSP1, ANK1, and FBXO11. Nonsynonymous rare and low-frequency mutations in four genes including SERPINF1 (PEDF), ZNF30, CD34, and SLC5A9, and non-intronic rare and low-frequency mutations in genes OPRD1, HSD17B3 and one lincRNA were significantly associated with SB. One identified pathway related to hypoxia-inducible factor (HIF) regulation, whose 83 nonsynonymous rare and low-frequency variants on 10 genes were significantly linked to SB as well. Four additional genes, and two pathways related to vasopressin-regulated water metabolism and cellular hexose transport, also were strongly associated with SB. This study represents the first investigation of genetic factors for SB in an American Indian population that has high risk for suicide. Our study suggests that bivariate association analysis between comorbid disorders can increase statistical power; and rare and low-frequency variant analysis in a high-risk population enabled by whole-genome sequencing has the potential to identify novel genetic factors. Although such findings may be population specific, rare functional mutations relating to PEDF and HIF regulation align with past reports and suggest a biological mechanism for suicide risk and a potential therapeutic target for intervention.

Comorbidity of anxiety/affective, conduct/antisocial, attention deficit, and alcohol use disorders with suicidal behaviors in an American Indian community sample of adults and adolescents.

AIMS: To study the associations of anxiety/affective disorders, conduct/antisocial disorders (ASPD/CD), attention deficit disorders (ADHD), and alcohol use disorders (AUD) with suicidal behaviors in an American Indian (AI) community sample of adolescents and adults. METHODS: Participants were AI (360 adolescents, 925 adults) recruited from reservations who were assessed with the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). RESULTS: Among AI adults (mean age = 33 years), 17% percent reported lifetime experiences of suicidal thoughts (ideation and/or plans) and 14% reported suicidal acts (including either a suicide attempt history or verified death by suicide; n = 19 deaths). Among AI adolescents (mean age = 15 years), 20% experienced suicidal thoughts and 9% experienced suicidal acts (including 3 deaths). In logistic regression analyses, suicidal thoughts were significantly associated with lifetime diagnoses of affective disorder, CD and ADHD in adolescents, and with anxiety disorder, affective disorder, and ASPD/CD in adults. Suicidal acts were associated with affective disorder, ADHD, and alcohol drinking in adolescents and with anxiety disorder, ASPD/CD and AUD in adults. The number of comorbid disorders greatly increased the risk of both suicidal thoughts and acts among both adolescents and adults. CONCLUSIONS: In addition to affective disorders, both ADHD and CD in adolescents, and ASPD in adults, demonstrated an association with suicidal thoughts. Alcohol use by adolescents and AUD among adults also were associated with suicidal attempts in this AI sample. These findings suggest need for additional research and potential integration of alcohol in screening and intervention programs focused on the prevention of suicide among AI.

Use of a Fitbit-like device in rats: Sex differences, relation to EEG sleep, and use to measure the long-term effects of adolescent ethanol exposure.

BACKGROUND: Sleep difficulties and rhythm disturbances are some of the problems associated with adolescent binge drinking. Recently, animal models of alcohol-induced insomnia have been developed. However, studies in human subjects have recently focused not only on nighttime EEG findings but also on daytime sleepiness and disrupted activity levels as typically measured by activity tracking devices such as the "Fitbit." We sought to develop and test a Fitbit-like device (the "FitBite") in rats and use it to track rest-activity cycles following adolescent alcohol exposure. METHODS: The effects of 5 weeks of adolescent ethanol vapor or control conditions were evaluated in 48 male and female Wistar rats using FitBite activity while intoxicated, and during acute (24 h post-vapor exposure) and chronic withdrawal (4 weeks post-vapor exposure). Data were analyzed using activity count and cosinor analyses. Fourteen rats were subsequently implanted with cortical electrodes, and data from the FitBite were compared with EEG data to determine how well the FitBite could identify sleep and activity cycles. RESULTS: Female rats were generally more active than males, with higher circadian rhythm amplitudes and mesors (rhythm-adjusted means) across a 24-h period. There were significant correlations between EEG-estimated sleep and activity counts using the FitBite. When the rats were tested during intoxication after 4 weeks of ethanol vapor exposure, they had significantly less overall activity. Disruptions in circadian rhythm were also found with significant decreases in the circadian amplitude, mesor, and a later shift in the acrophase. At 24 h of ethanol withdrawal, rats had more episodes of activity with shorter durations during the daytime, when rats are expected to spend more of their time sleeping. This effect remained at 4 weeks following withdrawal, but circadian rhythm disruptions were no longer present. CONCLUSIONS: A Fitbit-like device can be successfully used in rats to assess rest-activity cycles. Adolescent alcohol exposure produced circadian rhythm disturbances that were not observed after withdrawal. Fragmentation of ultradian rest-activity cycles during the light period was found at 24 h and 4 weeks after withdrawal and support data demonstrating the presence of sleep disturbance long after alcohol withdrawal.

Poor self-reported sleep quality associated with suicide risk in a community sample of American Indian adults.

Study Objectives: Although American Indian/Alaska Native (AI/AN) have high suicide rates few studies have systematically investigated sleep quality and its association with suicidal behaviors in AI/AN. This study is a cross-sectional investigation of self-reported sleep quality and suicidal behaviors in an adult AI population. Methods: A semi-structured interview was used to collect data on suicidal ideation, suicidal plans, and suicidal attempts and the Pittsburgh Sleep Quality Index (PSQI) was collected to assess sleep quality in American Indian adults. Results: In this sample (n = 477), 91 (19%) of the participants endorsed suicidal ideation (thoughts and plans), and 66 (14%) reported suicidal attempts, including four who subsequently died by suicide. More women reported suicidal thoughts or acts than men. Those endorsing suicidal thoughts slept fewer hours during the night, reported more nocturnal awakenings, and showed poorer subjective sleep quality according to PSQI total scores compared to those with no suicidal thoughts or acts. Participants with suicidal acts (n = 66) reported more bad dreams and higher PSQI total scores compared to those with no suicidal thoughts or acts. When those with any suicidal thoughts or acts (n = 157, 33%) were compared to those without, they were more likely to endorse nocturnal awakenings and bad dreams and demonstrated significantly higher PSQI total scores. Conclusions: Although additional research is needed to evaluate sleep disturbances as a proximal, causal risk factor for suicidal behaviors in AI, findings highlight need for further study of sleep as a warning sign and intervention tool for suicide prevention among American Indian adults.

Pleiotropic loci for cannabis use disorder severity in multi-ancestry high-risk populations.

Cannabis use disorder (CUD) is common and has in part a genetic basis. The risk factors underlying its development likely involve multiple genes that are polygenetic and interact with each other and the environment to ultimately lead to the disorder. Co-morbidity and genetic correlations have been identified between CUD and other disorders and traits in select populations primarily of European descent. If two or more traits, such as CUD and another disorder, are affected by the same genetic locus, they are said to be pleiotropic. The present study aimed to identify specific pleiotropic loci for the severity level of CUD in three high-risk population cohorts: American Indians (AI), Mexican Americans (MA), and European Americans (EA). Using a previously developed computational method based on a machine learning technique, we leveraged the entire GWAS catalog and identified 114, 119, and 165 potentially pleiotropic variants for CUD severity in AI, MA, and EA respectively. Ten pleiotropic loci were shared between the cohorts although the exact variants from each cohort differed. While majority of the pleiotropic genes were distinct in each cohort, they converged on numerous enriched biological pathways. The gene ontology terms associated with the pleiotropic genes were predominately related to synaptic functions and neurodevelopment. Notable pathways included Wnt/ß-catenin signaling, lipoprotein assembly, response to UV radiation, and components of the complement system. The pleiotropic genes were the most significantly differentially expressed in frontal cortex and coronary artery, up-regulated in adipose tissue, and down-regulated in testis, prostate, and ovary. They were significantly up-regulated in most brain tissues but were down-regulated in the cerebellum and hypothalamus. Our study is the first to attempt a large-scale pleiotropy detection scan for CUD severity. Our findings suggest that the different population cohorts may have distinct genetic factors for CUD, however they share pleiotropic genes from underlying pathways related to Alzheimer's disease, neuroplasticity, immune response, and reproductive endocrine systems.

Event-related Oscillations to Emotional Faces are Related to a History of Internalizing Disorders.

Event-related oscillations (EROs) may represent sensitive biomarkers or endophenotypes for disorders that underlie risk behaviors such as suicidal thoughts and actions. In this study, young adults of American Indian (AI) (n = 821) and Mexican American (MA) (n = 721) ancestry (age 18-30 yrs) were clinically assessed for internalizing and externalizing disorders, and an internalizing scale was generated by extracting core diagnostic items from 6 lifetime DSM5-compatible diagnoses (social phobia, panic disorder, agoraphobia, obsessive compulsive disorder, post-traumatic stress disorder, major depressive episode) and symptoms of suicidality. EROs were generated to sad, happy and neutral faces, and energy and phase locking of delta ERO oscillations were assessed in frontal areas. An increase in delta ERO energy was found in the frontal lead (FZ) following presentation of the sad facial expressions in those with a history of 10 or more internalizing symptoms compared to those with no symptoms. Increases in delta ERO energy in FZ were also associated with a diagnosis of major depressive disorder (MDD), but not with anxiety disorders or antisocial personality disorder/conduct disorders (ASP). Major depression was also associated with increases in cross-cortical phase-locking (FZ-PZ). A decrease in the percentage of correctly identified neutral faces also was seen among those with 10 or more internalizing symptoms compared to those without internalizing symptoms, and in those with anxiety disorders, but not in those with ASP or MDD as compared to their controls. These findings suggest ERO measures may represent important potential biomarkers of depressive disorders as well as risk indicators for suicidal behaviors.

Trauma, historical trauma, PTSD and suicide in an American Indian community sample.

AIMS: To study the associations between perceived historical trauma, current traumatic events, diagnoses of post-traumatic stress disorder (PTSD), and suicidal behaviors in an American Indian community sample. METHODS: Participants were American Indians recruited from reservations who were assessed with the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), as well as the Historical Loss Scale, Historical Loss Associated Symptoms Scale, and Stressful Life Events Scale. RESULTS: In data from 447 American Indian adults (mean age = 33 years), twenty percent reported lifetime experiences of suicidal thoughts (ideation and/or plans) and 14% reported suicidal acts, (including either a suicide attempt history or verified death by suicide (n = 4)). Diagnosis of PTSD and experience of assaultive trauma were each significantly associated with suicidal thoughts and acts, although assaultive trauma did not remain significant in models adjusting for gender and PTSD. High endorsement of symptoms associated with historical trauma was significantly associated with suicidal acts, and this remained significant when adjusting for gender and PTSD. CONCLUSIONS: PTSD and historical trauma have an association with suicide and suicidal attempts in this American Indian community. Although further research is needed to evaluate the causal nature of these relations, these findings suggest treatment and prevention programs for American Indian suicide may benefit from addressing issues related to feelings of historical losses, PTSD, and their associated symptomatology.

Age of onset and alcohol and cannabis use disorders among Mexican American young adults: Robust substance-specific effects of early use as a risk factor.

We investigated the substance-specific and cross-substance risk associated with early onset (before age 15) of drunkenness and cannabis use in the subsequent development of alcohol (AUD) and cannabis use disorder (CUD) in Mexican American young adults. Survival analyses employed Cox proportional hazards models for AUD and CUD, separately. In cross-risk analyses, we modeled estimates for those participants reporting lifetime use of both substances. Early onset of drunkenness and early onset of cannabis use were associated with shorter time to AUD and CUD, respectively, even after accounting for psychiatric disorders. While there were no cross-risk associations, adjusting for psychiatric disorders and early onset cannabis use attenuated the association of early drunkenness with AUD.

The clinical course of antisocial behaviors in men and women of three racial groups.

AIMS: To describe the clinical course and symptom profile of DSM-IV Antisocial Personality Disorder (ASPD) and the syndrome of Adult Antisocial Behavior Syndrome (AABS) and determine if they differ based on sex and race. METHODS: Using questions from a validated semi-structured interview, data were gathered from 2 independent family studies in: 1) American Indians (AI), and 2) European Americans (EA), African Americans (AA) (total n = 7171) who reported antisocial symptoms. RESULTS: Within these two samples 1148 (16%) individuals met ASPD criteria, 1932 (27%) met adult ASPD but not childhood conduct disorder (CD) (i.e., AABS). The clinical course of the antisocial behaviors studied did not differ based on race or sex; however, individual symptom counts, and age of onsets of those symptoms, were significantly different across the groups. Women reported fewer symptoms and at an older age (less fights, school suspensions/expulsions, arrests or jail time), than men but were more likely to run away from home. Those with ASPD vs. AABS had more symptoms overall including not experiencing remorse. AA and AI participants and those with ASPD, had more symptoms, and were more likely to be suspended/expelled from school and arrested at a younger age than EA. CONCLUSION: In these select samples, the order and sequence of antisocial behaviors did not differ by race, AASB vs. ASPD, or sex; however individual symptom endorsement did, with men (vs. women), those with ASPD (vs. AABS), AI and AA (vs. EA) reporting more suspensions/expulsions from school and arrests. This suggests further study of the possible role of race and sex in the consequences associated with antisocial syndromes is warranted.

Effects of genetic risk for alcohol dependence and onset of regular drinking on the progression to alcohol dependence: A polygenic risk score approach.

BACKGROUND: Prior studies have established the importance of genetic contributions to the etiology of alcohol dependence (AD), and suggested an early onset of alcohol use represents an initial marker of this genetic risk, which is associated with a more rapid progression to AD and increased risk for AD itself. Building on prior work, the current study examined whether the additive effects of AD risk variants predicted the rate of progression to AD from the onset of regular drinking, a drinking milestone with high clinical relevance to AD prevention. METHODS: Data from 1501 European-ancestry adults from the University of California - San Francisco Family Alcoholism Study were used to examine whether polygenic risk scores for AD (PRSAD) and age-at-onset of regular drinking contributed uniquely to the likelihood of having a lifetime AD diagnosis and the rate of progression from regular drinking to AD. Mixed effects logistic regression and Cox proportional hazards regression analyses were employed. RESULTS: Increases in PRSAD were associated with a faster progression from regular drinking to AD independent of age-at-onset of regular drinking. An independent effect of age-at-onset of regular drinking was also observed indicating that a one-year delay in regular drinking was associated with a 7% decrease in the hazard of progression to AD among drinkers with an early onset (≤ 18), but a 3% increase among drinkers with a late onset (> 18) of regular drinking. CONCLUSIONS: These results broaden our understanding of the contributions of measured genotypes underlying AD-risk on the etiology and clinical course of AD.

Extreme Binge Drinking During Adolescence: Associations With Subsequent Substance Use Disorders in American Indian and Mexican American Young Adults.

OBJECTIVE: This study collected retrospective data on adolescent binge drinking (ABD) (5 drinks for boys, 4 for girls per occasion at least once per month) and/or extreme adolescent binge drinking (EABD) (10 or more drinks per occasion at least once per month) and tested for associations with demographic and diagnostics variables including alcohol and other substance use disorders (AUD/SUD). METHODS: Cross-sectional data were collected from young adult (age 18-30 yrs) American Indians (AI) (n = 534) and Mexican Americans (MA) (n = 704) using a semi-structured diagnostic instrument. RESULTS: Thirty percent (30%) of the sample reported ABD and 21% reported EABD. Those having had monthly ABD were more likely to be AI and have less education; those having had EABD were more likely to be AI, male, younger, have less education and lower economic status compared to participants without ABD. ABD/EABD was associated with higher impulsivity, a family history of AUD, and lower level of response to alcohol (ORs = 1.0-2.0), as well as with adult AUD (ORs = 3.7-48), other substance use disorders (ORs = 3.5-9), and conduct disorder/ antisocial personality disorder (ORs = 2.0-2.6), but not with anxiety/depression. Monthly EABD further increased the odds of AUD/SUD. CONCLUSIONS: Although binge drinking was more common in AI compared to MA, there were little effects of race in individual risk factor analyses. Monthly ABD and EABD were common among these AI/MA as adolescents, and, as with other ethnic groups, these drinking patterns resulted in highly significant increases in the odds of developing alcohol and other substance use disorders in young adulthood.

The role of sex in the persistent effects of adolescent alcohol exposure on behavior and neurobiology in rodents.

Alcohol drinking is often initiated during adolescence, and this frequently escalates to binge drinking. As adolescence is also a period of dynamic neurodevelopment, preclinical evidence has highlighted that some of the consequences of binge drinking can be long lasting with deficits persisting into adulthood in a variety of cognitive-behavioral tasks. However, while the majority of preclinical work to date has been performed in male rodents, the rapid increase in binge drinking in adolescent female humans has re-emphasized the importance of addressing alcohol effects in the context of sex as a biological variable. Here we review several of the consequences of adolescent ethanol exposure in light of sex as a critical biological variable. While some alcohol-induced outcomes, such as non-social approach/avoidance behavior and sleep disruption, are generally consistent across sex, others are variable across sex, such as alcohol drinking, sensitivity to ethanol, social anxiety-like behavior, and induction of proinflammatory markers.

Chronic intermittent ethanol during adolescence and adulthood alters dendritic spines in the primary motor and visual cortex in rats.

Prolonged adolescent binge drinking can disrupt sleep quality and increase the likelihood of alcohol-induced sleep disruptions in young adulthood in rodents and in humans. Striking changes in spine density and morphology have been seen in many cortical and subcortical regions after adolescent alcohol exposure in rats. However, there is little known about the impact of alcohol exposure on dendritic spines in the same motor and sensory cortices that EEG sleep is typically recorded from in rats. The aim of this study is to investigate whether an established model of chronic intermittent ethanol vapor in rats that has been demonstrated to disrupt sleep during adolescence or adulthood, also significantly alters cortical dendritic spine density and morphology. To this end, adolescent and adult Wistar rats were exposed to 5 weeks of ethanol vapor or control air exposure. After a 13-day withdrawal, primary motor cortex (M1) and primary/secondary visual cortex (V1/V2) layer V dendrites were analyzed for differences in spine density and morphology. Spines were classified into four categories (stubby, long, filopodia, and mushroom) based on the spine length and the width of the spine head and neck. The main results indicate an age-specific effect of adolescent intermittent ethanol exposure decreasing spine density in the M1 cortex compared to age-matched controls. Reductions in the density of M1 long-shaped spine subclassifications were seen in adolescent ethanol-exposed rats, but not adult-exposed rats, compared to their air-controls. Irrespective of age, there was an overall reduction produced by ethanol exposure on the density of filopodia and the length of long-shaped spines in V1/V2 cortex as compared to their air-exposed controls. Together, these data add to growing evidence that some cortical circuits are vulnerable to the effects of alcohol during adolescence and begin to elucidate potential mechanisms that may influence brain plasticity following early alcohol use.

Childhood Experiences and High-Intensity Drinking Among American Indian and Alaska Native Adults: Findings From the 2000-2015 National Alcohol Surveys.

OBJECTIVE: The purpose of this study was to examine associations with high-intensity drinking (HID) in American Indian/Alaska Native (AI/AN) populations and compare them to White and other minority groups using four National Alcohol Surveys, 2000 to 2015 (total N = 29,571; AI/ANs = 434). METHOD: Current drinking and HID (8+ and 12+ drinks on any day) from maximum drinks in the prior 12 months were analyzed with independent variables and race/ethnicity (AI/AN, non-Hispanic White, and other racial/ethnic groups combined). Adjusted logistic regression models comprised gender, age, marital status, employment, education, survey year, rurality, and especially, childhood trauma (physical/sexual abuse), and biological family alcohol problem history (each dichotomous). RESULTS: In adjusted population models, Whites had twice the odds of current drinking as AI/ANs, with no difference between other racial/ethnic groups and AI/ANs. Descriptively, AI/AN drinkers consumed at higher intensity levels than other groups, with higher prevalence of childhood trauma and family problem drinking than others. However, on a population basis, adjusting for all factors, apparent differences between AI/AN and White HID were eliminated; other minority groups together, compared with AI/ANs, showed lower odds of consuming 8+ drinks. CONCLUSIONS: AI/ANs had a higher prevalence of childhood trauma and family alcohol problems as well as lower current drinking likelihood compared with Whites. In adjusted population models, the combined other minorities group was less likely to ever consume 8+ drinks than AI/ANs. In all populations, childhood trauma and family alcohol problems increased the risk of HID, strongly so in AI/ANs. Addressing childhood trauma and family problems is important among AI/ANs to break generational cycles of drinking extreme amounts per occasion.

Long tracks of homozygosity predict the severity of alcohol use disorders in an American Indian population.

Runs of homozygosity (ROH) arise when an individual inherits two copies of the same haplotype segment. While ROH are ubiquitous across human populations, Native populations-with shared parental ancestry arising from isolation and endogamy-can carry a substantial enrichment for ROH. We have been investigating genetic and environmental risk factors for alcohol use disorders (AUD) in a group of American Indians (AI) who have higher rates of AUD than the general U. S. population. Here we explore whether ROH might be associated with incidence and severity of AUD in this admixed AI population (n = 742) that live on geographically contiguous reservations, using low-coverage whole genome sequences. We have found that the genomic regions in the ROH that were identified in this population had significantly elevated American Indian heritage compared with the rest of the genome. Increased ROH abundance and ROH burden are likely risk factors for AUD severity in this AI population, especially in those diagnosed with severe and moderate AUD. The association between ROH and AUD was mostly driven by ROH of moderate lengths between 1 and 2 Mb. An ROH island on chromosome 1p32.3 and a rare ROH pool on chromosome 3p12.3 were found to be significantly associated with AUD severity. They contain genes involved in lipid metabolism, oxidative stress and inflammatory responses; and OSBPL9 was found to reside on the consensus part of the ROH island. These data demonstrate that ROH are associated with risk for AUD severity in this AI population.

Common genetic substrates of alcohol and substance use disorder severity revealed by pleiotropy detection against GWAS catalog in two populations.

Alcohol and other substance use disorders (AUD and SUD) are complex diseases that are postulated to have a polygenic inheritance and are often comorbid with other disorders. The comorbidities may arise partially through genetic pleiotropy. Identification of specific gene variants accounting for large parts of the variance in these disorders has yet to be accomplished. We describe a flexible strategy that takes a variant-trait association database and determines if a subset of disease/straits are potentially pleiotropic with the disorder under study. We demonstrate its usage in a study of use disorders in two independent cohorts: alcohol, stimulants, cannabis (CUD), and multi-substance use disorders (MSUD) in American Indians (AI) and AUD and CUD in Mexican Americans (MA). Using a machine learning method with variants in GWAS catalog, we identified 229 to 246 pleiotropic variants for AI and 153 to 160 for MA for each SUD. Inflammation was the most enriched for MSUD and AUD in AIs. Neurological disorder was the most significantly enriched for CUD in both cohorts, and for AUD and stimulants in AIs. Of the select pleiotropic genes shared among substances-cohorts, multiple biological pathways implicated in SUD and other psychiatric disorders were enriched, including neurotrophic factors, immune responses, extracellular matrix, and circadian regulation. Shared pleiotropic genes were significantly up-regulated in brain regions playing important roles in SUD, down-regulated in esophagus mucosa, and differentially regulated in adrenal gland. This study fills a gap for pleiotropy detection in understudied admixed populations and identifies pleiotropic variants that may be potential targets of interest for SUD.

Correction to: Effect of a dual orexin receptor antagonist (DORA-12) on sleep and event-related oscillations in rats exposed to ethanol vapor during adolescence.

The title of this article is "Effect of a dual orexin receptor antagonist (DORA-12) on sleep and event-related oscillations in rats exposed to ethanol vapor during adolescence".

Delta Event-Related Oscillations Are Related to a History of Extreme Binge Drinking in Adolescence and Lifetime Suicide Risk.

Alcohol exposure typically begins in adolescence, and heavy binge drinking is associated with health risk behaviors. Event-related oscillations (EROs) may represent sensitive biomarkers or endophenotypes for early alcohol exposure as well as other risk behaviors such as suicidal thoughts and actions. In this study, young adults (age 18-30 years) of American Indian (AI) (n = 479) and Mexican American (MA) (n = 705) ancestry were clinically assessed, and EROs were generated to happy, sad and neutral faces. Extreme adolescent binge drinking (10+ drinks) was common (20%) in this population of AI/MA and associated with a significantly increased risk of a lifetime history of suicidal acts (SA, suicide attempts, deaths) but not suicidal thoughts (ST, ideation, plans). ST were reported among MA participants, whereas SA were more common among AI young adults. Extreme adolescent binge drinking was also associated with errors in detection of sad and neutral faces, increases in delta ERO energy, and decreases in phase locking (PL), particularly in parietal areas. A lifetime history of ST was associated with increases in delta ERO energy and PL, whereas SA were associated with decreases in both. These studies suggest that ERO measures may represent important potential biomarkers of adolescent extreme binge drinking and risk for suicidal behaviors.