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.

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.

Prevention of Underage Drinking on California Indian Reservations Using Individual- and Community-Level Approaches.

OBJECTIVES: To evaluate combined individual- and community-level interventions to reduce underage drinking by American Indian/Alaska Native (AI/AN) youths on rural California Indian reservations. METHODS: Individual-level interventions included brief motivational interviewing and psychoeducation for Tribal youths. Community-level interventions included community mobilization and awareness activities, as well as restricting alcohol sales to minors. To test effects, we compared 7 waves of California Healthy Kids Survey data (2002-2015) for 9th- and 11th-grade AI/AN and non-AI/AN students in intervention area schools with California AI/AN students outside the intervention area (n = 617, n = 33 469, and n = 976, respectively). RESULTS: Pre- to postintervention mean past 30-day drinking frequency declined among current drinkers in the intervention group (8.4-6.3 days) relative to comparison groups. Similarly, heavy episodic drinking frequency among current drinkers declined in the intervention group (7.0-4.8 days) versus the comparison groups. CONCLUSIONS: This study documented significant, sustained past 30-day drinking or heavy episodic drinking frequency reductions among AI/AN 9th- and 11th-grade current drinkers in rural California Indian reservation communities exposed to multilevel interventions. Public Health Implications. Multilevel community-partnered interventions can effectively reduce underage alcohol use in this population.

Whole genome sequence study of cannabis dependence in two independent cohorts.

Recent advances in genome wide sequencing techniques and analytical methods allow for more comprehensive examinations of the genome than microarray-based genome-wide association studies (GWAS). The present report provides the first application of whole genome sequencing (WGS) to identify low frequency variants involved in cannabis dependence across two independent cohorts. The present study used low-coverage whole genome sequence data to conduct set-based association and enrichment analyses of low frequency variation in protein-coding regions as well as regulatory regions in relation to cannabis dependence. Two cohorts were studied: a population-based Native American tribal community consisting of 697 participants nested within large multi-generational pedigrees and a family-based sample of 1832 predominantly European ancestry participants largely nested within nuclear families. Participants in both samples were assessed for Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) lifetime cannabis dependence, with 168 and 241 participants receiving a positive diagnosis in each sample, respectively. Sequence kernel association tests identified one protein-coding region, C1orf110 and one regulatory region in the MEF2B gene that achieved significance in a meta-analysis of both samples. A regulatory region within the PCCB gene, a gene previously associated with schizophrenia, exhibited a suggestive association. Finally, a significant enrichment of regions within or near genes with multiple splice variants or involved in cell adhesion or potassium channel activity were associated with cannabis dependence. This initial study demonstrates the potential utility of low pass whole genome sequencing for identifying genetic variants involved in the etiology of cannabis use disorders.

Cardiovascular disease risks in adult Native and Mexican Americans with a history of alcohol use disorders: association with cardiovascular autonomic control.

Hypertension and obesity are serious health problems that have been associated with an increased risk of cardiovascular disease (CVD). We recently showed a relationship between hypertension, obesity and cardiovagal control in a sample of Native and Mexican Americans at high risk of alcohol use disorders (AUD). While studies have shown that Native and Mexican Americans exhibit high rates of AUD, the consequences of AUD on CVD risk factors and their relationship with cardiovascular autonomic control is not well understood in these ethnic groups. This study investigated whether an association could be demonstrated between cardiovascular autonomic control and several CVD risk factors in Native and Mexican American men and women (n = 228) who are literate in English and are residing legally in San Diego County. Participants with lifetime history of AUD showed higher rates of systolic and diastolic hypertension and obesity than participants without lifetime AUD. Lifetime AUD was significantly associated with reduced HR response to deep breathing (HRDB) measure of cardiovagal control, higher current drinking quantity, and obesity. Reduced HRDB was also associated with increased systolic pre-hypertension or hypertension (pre-/hypertension) and with higher diastolic blood pressure in a linear regression model that included several diagnostic and demographic variables. HRDB and time- and frequency-domain measures of cardiovagal control were significantly reduced in participants with diastolic pre-/hypertension. These data suggest that lower cardiovagal control may play a role in the prevalence of systolic and diastolic pre-/hypertension in a community sample with a history of alcohol and substance use disorders.

The clinical course of DSM-5 alcohol use disorders in young adult native and Mexican Americans.

BACKGROUND AND OBJECTIVES: To determine if the clinical course of DSM-5 alcohol use disorders (AUD) in select populations of young adults (18-30 years) differed based on gender, diagnostic severity (mild, moderate, severe), and ethnicity. METHODS: Native Americans (NA) and Mexican Americans (MA) (n = 1,129) were recruited from the community and completed a structured diagnostic interview. Participants with DSM-5 AUDs were compared based on gender, severity of the disorder (mild, moderate, severe), and ethnicity for differences in drinking levels, as well as the clinical course of AUD as defined by the occurrence and sequence of 36 alcohol-related life events. RESULTS: Seventy percent of the NA men, 64% of the NA women, 56% of the MA men, and 42% of the MA women met lifetime diagnostic criteria for a DSM-5 AUD. NA reported more alcohol-related life events and at an earlier age than MA. A high degree of similarity in the clinical course was found between men and women and between those with severe or moderate disorder, but not with those with mild disorder. CONCLUSIONS: NA had higher drinking levels and more alcohol problems at an earlier age than MA. A similar clinical course was seen based on gender and ethnicity in these young adults, but not based on diagnostic severity. SCIENTIFIC SIGNIFICANCE: The DSM-5 mild AUD category differs from the moderate and severe categories on drinking history, clinical course, gender, and ethnic distribution. Mild AUD may not be in the same clinical continuum as moderate and severe AUD in these populations.

Off-premise alcohol outlets on and around tribal land: risks for rural California Indian youth.

Investigating the alcohol environment for rural American Indian youth, we conducted 70 interviews with leading members and youth representatives of nine Southern California tribes. We also conducted brief observations in all 13 stores licensed to sell alcohol on and close to the reservation lands of the nine tribes. Underage youth may obtain alcoholic beverages at stores either directly through illegal sales to minors or indirectly through social sources. Stores are also environments within which alcoholic beverages and heavy drinking may become normalized for youth. Limitations and implications for convenience store-based prevention research on alcohol retail environment for youth in rural populations areas are discussed.

Associations between a history of binge drinking during adolescence and self-reported responses to alcohol in young adult Native and Mexican Americans.

BACKGROUND: Binge drinking during adolescence is common and may predict increased drinking in young adulthood and enhanced risk of alcohol dependence. Variation in level of response to the hedonic and adverse effects of alcohol is in part an inherited factor that may also influence its use, abuse, and dependence. This study investigated, in young adults, whether an association could be demonstrated between variation in self-reported responses to alcohol and a history of binge drinking during adolescence. METHODS: Young adult (18 to 30 years, n = 790) Native Americans and Mexican Americans were recruited from the community and completed a structured diagnostic interview. Response to alcohol was indexed using the expectation version of the Subjective High Assessment Scale (SHAS-E). An adolescent history of regular binge drinking was defined as drinking 5 or more drinks for boys and 4 or more drinks for girls per drinking occasion at least once a month during their highest drinking period prior to the age of 18. RESULTS: An adolescent history of regular binge drinking was found to be associated with a lower level of self-reported responses to the negative aspects of alcohol intoxication (feeling terrible) as well as to the overall level of intoxication, but not to the positive impressions of intoxication (feeling great) on the SHAS-E. A history of regular adolescent binge drinking was also correlated with less feelings of the "terrible" and "total" effects of alcohol, as indexed by the SHAS-E, in a linear regression model that included several diagnostic and demographic variables such as a history of conduct disorder and current levels of drinking. CONCLUSIONS: These data suggest that a history of adolescent binge drinking is associated with a reduction in the self-reported level of intoxication in young adulthood, a factor that could theoretically lead to increased risk of alcohol dependence.

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.

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.

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.

Depression symptoms associated with cannabis dependence in an adolescent American Indian community sample.

BACKGROUND: Depression and substance use disorders, including cannabis dependence, arise during adolescence, are frequently comorbid, and represent major health burdens in the general US population. Yet little is known about the association of depression symptoms with cannabis and other substance use and use disorders in Native American adolescents. OBJECTIVE: To investigate the comorbidity of cannabis use and depression symptoms in Native American adolescents. METHODS: This study used the Children's Semi-Structured Assessment for the Genetics of Alcoholism (Adolescent Version) to obtain lifetime DSM-III-R diagnoses from a community sample of 202 (98 boys, 104 girls) American Indian adolescents living on contiguous reservations. RESULTS: Thirteen percent of boys and 38% of girls had a lifetime DSM-III-R major depression disorder (MDD) independent of substance use. Fifteen percent of boys and 41% of girls had a major depression episode (MDE) either coincident with or independent of cannabis use. MDE and several individual depression symptoms were significantly associated with cannabis dependence in boys but not in girls. The median ages of onset of MDE were the same in the boys and girls who had experienced both depression and cannabis use. CONCLUSIONS: These findings suggest that the association of depression with cannabis dependence is more significant in boys than girls in this population of adolescents. SCIENTIFIC SIGNIFICANCE: Understanding comorbidity between depression and cannabis use is important in order to disentangle the etiological relationship between the two and also for designing more effective treatment and prevention strategies, particularly in Native Americans who are at high risk for both disorders.

Implementing a reward and reminder underage drinking prevention program in convenience stores near Southern California American Indian reservations.

BACKGROUND: Underage drinking is associated with a number of social and public health consequences. Preventing access to alcohol is one approach to reducing underage drinking. OBJECTIVES: This study assesses the efficacy of a culturally tailored "reward and reminder" program aimed at reducing convenience store alcohol sales to youth living on or near nine American Indian reservations. METHODS: First, tribal council proclamations were sought to support underage drinking prevention, including reward and reminder efforts. Then, decoys (volunteers over 21 years of age but judged to look younger) attempted to purchase alcohol without identification. Clerks who asked for identification were given "rewards" (gift cards and congratulatory letters), whereas clerks who did not were given "reminders" of the law regarding sales to minors. Following an initial baseline of 12 purchase attempts, three repeated reward and reminder visits were made to 13 convenience stores selling alcohol within 10 miles of the reservations (n = 51 total attempts). RESULTS: Five of nine tribal councils passed resolutions in support of the program. The baseline sales rate without requesting ID was 33%. Similarly, 38% of stores in the first reward and reminder visit round failed to request identification. However, in the following two reward and reminder rounds, 0% of the stores failed to request identification. CONCLUSIONS: These results indicate that environmental community-level underage drinking prevention strategies to reduce alcohol sales near rural reservations are feasible and can be effective. SCIENTIFIC SIGNIFICANCE: Environmental prevention strategies within reservation communities support integrated supply and demand reduction models for reducing underage drinking.

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.

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.

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.

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.

Item response theory analysis of binge drinking and its relationship to lifetime alcohol use disorder symptom severity in an American Indian community sample.

BACKGROUND: Item response theory (IRT) has been used to examine alcohol use disorder (AUD) symptoms and their psychometric properties but has not been previously applied to AUD symptoms from an American Indian sample. METHODS: Lifetime DSM-IV AUD symptoms and binge drinking (5+ drinks men/4+ drinks women) at ≥1, ≥4, ≥8, and ≥15 days per month during the period of heaviest lifetime drinking criteria were assessed in 530 American Indian participants. Exploratory factor analysis was used to examine the factor structure of the 10 AUD symptoms and each alcohol consumption criterion. Two-parameter IRT models generated marginal maximum likelihood estimates for discrimination (a) and threshold (b) parameters for 10 DSM-IV AUD symptoms and each consumption criterion. Differential item functioning (DIF) analysis was used to assess AUD symptom severity in groups defined by gender and age at interview. RESULTS: The AUD symptoms of "Withdrawal" and "Activities Given Up" were the most severe symptoms. "Tolerance" and "Social/Interpersonal Problems" were the least severe. All AUD symptoms fell on the moderate portion of the severity continuum, except "Withdrawal," which fell at the lower end of the severe portion. The consumption criterion of 5+/4+ (male/female) at ≥8 times per month demarcated the portion of the severity continuum where AUD symptoms began to occur at a probability of 50%. DIF analysis showed significant gender and age at interview differences for "Hazardous Use,""Tolerance," and "Activities Given Up," but not for the other AUD symptoms. CONCLUSIONS: In this American Indian community sample, alcohol abuse and dependence did not represent distinct disorders. Only one AUD symptom was found outside the moderate portion of the underlying AUD severity continuum. Drinking 5+/4+ (male/female) drinks at a frequency of ≥8 times per month during the period of heaviest lifetime drinking was found to function well as both a risk and a diagnostic criterion for lifetime DSM-IV AUD. DSM-IV AUD symptom criteria, as currently assessed, may be limited in their ability to capture the full range of symptom severity of AUDs, at least in this high-risk population.

Association of alcohol dehydrogenase genes with alcohol-related phenotypes in a Native American community sample.

BACKGROUND: Previous linkage studies, including a study of the Native American population described in the present report, have provided evidence for linkage of alcohol dependence and related traits to chromosome 4q near a cluster of alcohol dehydrogenase (ADH) genes, which encode enzymes of alcohol metabolism. METHODS: The present study tested for associations between alcohol dependence and related traits and 22 single-nucleotide polymorphisms (SNPs) spanning the 7 ADH genes. Participants included 586 adult men and women recruited from 8 contiguous Native American reservations. A structured interview was used to assess DSM-III-R alcohol dependence criteria as well as a set of severe alcohol misuse symptoms and alcohol withdrawal symptoms. RESULTS: No evidence for association with the alcohol dependence diagnosis was observed, but an SNP in exon 9 of ADH1B (rs2066702; ADH1B*3) and an SNP at the 5' end of ADH4 (rs3762894) showed significant evidence of association with the presence of withdrawal symptoms (p = 0.0018 and 0.0012, respectively). Further, a haplotype analysis of these 2 SNPs suggested that the haplotypes containing either of the minor alleles were protective against alcohol withdrawal relative to the ancestral haplotype (p = 0.000006). CONCLUSIONS: These results suggest that variants in the ADH1B and ADH4 genes may be protective against the development of some symptoms associated with alcohol dependence.