Examining associations between genetic and neural risk for externalizing behaviors in adolescence and early adulthood.

BACKGROUND: Researchers have identified genetic and neural risk factors for externalizing behaviors. However, it has not yet been determined if genetic liability is conferred in part through associations with more proximal neurophysiological risk markers. METHODS: Participants from the Collaborative Study on the Genetics of Alcoholism, a large, family-based study of alcohol use disorders were genotyped and polygenic scores for externalizing (EXT PGS) were calculated. Associations with target P3 amplitude from a visual oddball task (P3) and broad endorsement of externalizing behaviors (indexed via self-report of alcohol and cannabis use, and antisocial behavior) were assessed in participants of European (EA; N = 2851) and African ancestry (AA; N = 1402). Analyses were also stratified by age (adolescents, age 12-17 and young adults, age 18-32). RESULTS: The EXT PGS was significantly associated with higher levels of externalizing behaviors among EA adolescents and young adults as well as AA young adults. P3 was inversely associated with externalizing behaviors among EA young adults. EXT PGS was not significantly associated with P3 amplitude and therefore, there was no evidence that P3 amplitude indirectly accounted for the association between EXT PGS and externalizing behaviors. CONCLUSIONS: Both the EXT PGS and P3 amplitude were significantly associated with externalizing behaviors among EA young adults. However, these associations with externalizing behaviors appear to be independent of each other, suggesting that they may index different facets of externalizing.

Intraindividual variability in brain activation-A novel correlate of obesity risk among female college students.

There are published data describing impairments in the brain function of adolescents or young adults who have a genetic or familial predisposition for obesity. From these descriptions, it is often assumed that the impairments are appropriately captured by a central tendency estimate and therefore consistently detectable. The present study questions this assumption and shows that the variability in brain function over the time course of a cognitive task is a better predictor of familial risk than its central tendency. Sixty-nine female young adults lacking an obese parent and 24 female young adults with an obese parent were compared on the average amplitude and inter-trial variability (ITV) in amplitude of their P300 electroencephalographic responses to rarely-occurring stimuli during a selective attention task. Simple group comparisons revealed statistically significant findings with effect sizes that were markedly greater for analyses of P300 ITV versus P300 average amplitude. It is suggested that the elevation in P300 ITV among young adults with familial risk indicates temporal instability in systems responsible for the maintenance of attention. These fluctuations may episodically disrupt their attention to satiety cues as well as other cues that influence behavior regulation.

Predicting risk for Alcohol Use Disorder using longitudinal data with multimodal biomarkers and family history: a machine learning study.

Predictive models have succeeded in distinguishing between individuals with Alcohol use Disorder (AUD) and controls. However, predictive models identifying who is prone to develop AUD and the biomarkers indicating a predisposition to AUD are still unclear. Our sample (n = 656) included offspring and non-offspring of European American (EA) and African American (AA) ancestry from the Collaborative Study of the Genetics of Alcoholism (COGA) who were recruited as early as age 12 and were unaffected at first assessment and reassessed years later as AUD (DSM-5) (n = 328) or unaffected (n = 328). Machine learning analysis was performed for 220 EEG measures, 149 alcohol-related single nucleotide polymorphisms (SNPs) from a recent large Genome-wide Association Study (GWAS) of alcohol use/misuse and two family history (mother DSM-5 AUD and father DSM-5 AUD) features using supervised, Linear Support Vector Machine (SVM) classifier to test which features assessed before developing AUD predict those who go on to develop AUD. Age, gender, and ancestry stratified analyses were performed. Results indicate significant and higher accuracy rates for the AA compared with the EA prediction models and a higher model accuracy trend among females compared with males for both ancestries. Combined EEG and SNP features model outperformed models based on only EEG features or only SNP features for both EA and AA samples. This multidimensional superiority was confirmed in a follow-up analysis in the AA age groups (12-15, 16-19, 20-30) and EA age group (16-19). In both ancestry samples, the youngest age group achieved higher accuracy score than the two other older age groups. Maternal AUD increased the model's accuracy in both ancestries' samples. Several discriminative EEG measures and SNPs features were identified, including lower posterior gamma, higher slow wave connectivity (delta, theta, alpha), higher frontal gamma ratio, higher beta correlation in the parietal area, and 5 SNPs: rs4780836, rs2605140, rs11690265, rs692854, and rs13380649. Results highlight the significance of sampling uniformity followed by stratified (e.g., ancestry, gender, developmental period) analysis, and wider selection of features, to generate better prediction scores allowing a more accurate estimation of AUD development.

A genome-wide association study of interhemispheric theta EEG coherence: implications for neural connectivity and alcohol use behavior.

Aberrant connectivity of large-scale brain networks has been observed among individuals with alcohol use disorders (AUDs) as well as in those at risk, suggesting deficits in neural communication between brain regions in the liability to develop AUD. Electroencephalographical (EEG) coherence, which measures the degree of synchrony between brain regions, may be a useful measure of connectivity patterns in neural networks for studying the genetics of AUD. In 8810 individuals (6644 of European and 2166 of African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Multi-Trait Analyses of genome-wide association studies (MTAG) on parietal resting-state theta (3-7 Hz) EEG coherence, which previously have been associated with AUD. We also examined developmental effects of GWAS findings on trajectories of neural connectivity in a longitudinal subsample of 2316 adolescent/young adult offspring from COGA families (ages 12-30) and examined the functional and clinical significance of GWAS variants. Six correlated single nucleotide polymorphisms located in a brain-expressed lincRNA (ENSG00000266213) on chromosome 18q23 were associated with posterior interhemispheric low theta EEG coherence (3-5 Hz). These same variants were also associated with alcohol use behavior and posterior corpus callosum volume, both in a subset of COGA and in the UK Biobank. Analyses in the subsample of COGA offspring indicated that the association of rs12954372 with low theta EEG coherence occurred only in females, most prominently between ages 25 and 30 (p < 2 × 10-9). Converging data provide support for the role of genetic variants on chromosome 18q23 in regulating neural connectivity and alcohol use behavior, potentially via dysregulated myelination. While findings were less robust, genome-wide associations were also observed with rs151174000 and parieto-frontal low theta coherence, rs14429078 and parieto-occipital interhemispheric high theta coherence, and rs116445911 with centro-parietal low theta coherence. These novel genetic findings highlight the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Evaluating risk for alcohol use disorder: Polygenic risk scores and family history.

BACKGROUND: Early identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD. METHODS: We studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH-). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity. RESULTS: AUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E-05 ) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E-08 ) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E-04 ) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p-values ≤6.7E-11 ). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p-values ≤6.8E-10 ). CONCLUSIONS: Both PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits.

Altered brain activation in uncomplicated pediatric obesity: The second moment is more sensitive than the first.

Traditionally, studies of the neurocognitive correlates of obesity have computed a central tendency across trials of a task to estimate the functional abilities of individual members of obese and non-obese groups. This computation assumes that the correlate is stable over time-a questionable assumption when individuals are impulsive, periodically inattentive, and capable of overcompensation following awareness of failure. The present investigation departs from the tradition by focusing on the second moment, or variability, in brain activation during a simple selective attention task. It compared 124 non-obese and 80 obese teenaged girls on the across-trial average amplitude and inter-trial variability (ITV) of a sensitive biomarker of attention, the P300 event-related electroencephalographic potential. It found that P300 ITV outperformed P300 average amplitude in differentiating the groups. Further, it found that the elevated P300 ITV among obese teenagers was associated with other indicators of impulsivity and inattention as well as slower reaction times and a trend toward more variable reaction times. Future studies should investigate the value of P300 ITV as an objective and sensitive endpoint for cognitive training focused on improving the attention skills of obese children.

Neural Responses to Signals for Behavior Change: Greater Within-Person Variability is Associated With Risk Factors for Substance Dependence.

BACKGROUND: An impaired ability to change behavior in the face of cues indicating a need for change is one means of defining risk for substance dependence. The present study used a cognitive task administered in a laboratory as a model of this process. It focused on 2 known and related correlates of risk (conduct disorder, borderline personality disorder) and examined their associations with reactivity to cues requesting a change in motor behavior. METHODS: A total of 224 teenagers, 14 to 19 years of age, performed a task during which white noise bursts were used to cue a requirement to reverse the mapping of right and left key press responses onto high- and low-frequency pure tones during a subsequent trial block. The amplitude of the P300 electroencephalographic (EEG) response to each cue was summarized by calculating its across-trial average as well as its intertrial variability (ITV). In addition, the number of motor response reversal failures (perseveration errors) was calculated. RESULTS: The ITV of the P300 response to cues for behavior change was superior to its average amplitude in revealing associations with risk: It was significantly greater among teenagers with more conduct problems and more borderline personality disorder symptoms in comparison with their less-affected peers. ITV was also positively correlated with perseveration errors. No group differences were found in P300 amplitude averaged over trials. CONCLUSIONS: The findings suggest that the measurement of intertrial variability in brain activity may be more valuable than the average level for revealing neurophysiological differences associated with impulsivity and personality risk factors for dependence. EEG measures may be particularly valuable in this context because they offer superior temporal resolution and signal-to-noise characteristics.

Density and Dichotomous Family History Measures of Alcohol Use Disorder as Predictors of Behavioral and Neural Phenotypes: A Comparative Study Across Gender and Race/Ethnicity.

BACKGROUND: Family history (FH) is an important risk factor for the development of alcohol use disorder (AUD). A variety of dichotomous and density measures of FH have been used to predict alcohol outcomes; yet, a systematic comparison of these FH measures is lacking. We compared 4 density and 4 commonly used dichotomous FH measures and examined variations by gender and race/ethnicity in their associations with age of onset of regular drinking, parietal P3 amplitude to visual target, and likelihood of developing AUD. METHODS: Data from the Collaborative Study on the Genetics of Alcoholism (COGA) were utilized to compute the density and dichotomous measures. Only subjects and their family members with DSM-5 AUD diagnostic information obtained through direct interviews using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) were included in the study. Area under receiver operating characteristic curves were used to compare the diagnostic accuracy of FH measures at classifying DSM-5 AUD diagnosis. Logistic and linear regression models were used to examine associations of FH measures with alcohol outcomes. RESULTS: Density measures had greater diagnostic accuracy at classifying AUD diagnosis, whereas dichotomous measures presented diagnostic accuracy closer to random chance. Both dichotomous and density measures were significantly associated with likelihood of AUD, early onset of regular drinking, and low parietal P3 amplitude, but density measures presented consistently more robust associations. Further, variations in these associations were observed such that among males (vs. females) and Whites (vs. Blacks), associations of alcohol outcomes with density (vs. dichotomous) measures were greater in magnitude. CONCLUSIONS: Density (vs. dichotomous) measures seem to present more robust associations with alcohol outcomes. However, associations of dichotomous and density FH measures with different alcohol outcomes (behavioral vs. neural) varied across gender and race/ethnicity. These findings have great applicability for alcohol research examining FH of AUD.

Multivariate Analyses Reveal Biological Components Related to Neuronal Signaling and Immunity Mediating Electroencephalograms Abnormalities in Alcohol-Dependent Individuals from the Collaborative Study on the Genetics of Alcoholism Cohort.

BACKGROUND: The underlying molecular mechanisms associated with alcohol use disorder (AUD) risk have only been partially revealed using traditional approaches such as univariate genomewide association and linkage-based analyses. We therefore aimed to identify gene clusters related to Electroencephalograms (EEG) neurobiological phenotypes distinctive to individuals with AUD using a multivariate approach. METHODS: The current project adopted a bimultivariate data-driven approach, parallel independent component analysis (para-ICA), to derive and explore significant genotype-phenotype associations in a case-control subset of the Collaborative Study on the Genetics of Alcoholism (COGA) dataset. Para-ICA subjects comprised N = 799 self-reported European Americans (367 controls and 432 AUD cases), recruited from COGA, who had undergone resting EEG and genotyping. Both EEG and genomewide single nucleotide polymorphism (SNP) data were preprocessed prior to being subjected to para-ICA in order to derive genotype-phenotype relationships. RESULTS: From the data, 4 EEG frequency and 4 SNP components were estimated, with 2 significantly correlated EEG-genetic relationship pairs. The first such pair primarily represented theta activity, negatively correlated with a genetic cluster enriched for (but not limited to) ontologies/disease processes representing cell signaling, neurogenesis, transmembrane drug transportation, alcoholism, and lipid/cholesterol metabolism. The second component pair represented mainly alpha activity, positively correlated with a genetic cluster with ontologies similarly enriched as the first component. Disease-related enrichments for this component revealed heart and autoimmune disorders as top hits. Loading coefficients for both the alpha and theta components were significantly reduced in cases compared to controls. CONCLUSIONS: Our data suggest plausible multifactorial genetic components, primarily enriched for neuronal/synaptic signaling/transmission, immunity, and neurogenesis, mediating low-frequency alpha and theta abnormalities in alcohol addiction.

HIV/AIDS and an overweight body mass are associated with excessive intra-individual variability in response preparation.

Factors other than HIV/AIDS may influence the cognitive function of patients living with this disease. The present study tested the influence of a common comorbid problem-an overweight body mass. It also examined intra-task variabilities in performance and brain activation as potentially more sensitive indicators of dysfunction than their mean levels. One-hundred seventy-eight participants were recruited and categorized by HIV-1 serostatus (-/+) and body mass (BMI < 26/≥ 26 kg/m2). They performed a simple time estimation task during which response time accuracy and electroencephalographic readiness potentials were recorded. A few hours later, they completed a battery of tests measuring balance and gait. The analyses revealed an advantage of variability over the mean in differentiating groups: the presence of HIV-1 and an overweight body mass were independently and additively associated with greater variability across trials in readiness potential amplitude and response accuracy. The analysis also showed that intra-task variability in the readiness potential, but not in response accuracy, was predictive of decrements in single and tandem leg balance and gait velocity. The present findings suggest that an elevated body mass is associated with, and may contribute to, problems in brain function and motor behavior experienced by patients in the current era. The findings recommend a careful consideration of the manner in which these problems are measured. When the problems are episodic and subtle, measures of central tendency may be less than ideal.

Challenges in the Detection of Working Memory and Attention Decrements among Overweight Adolescent Girls.

BACKGROUND: The present study is unique in employing unusually difficult attention and working memory tasks to reveal subtle cognitive decrements among overweight/obese adolescents. It evaluated novel measures of background electroencephalographic (EEG) activity during one of the tasks and tested correlations of these and other measures with psychological and psychiatric predictors of obesity maintenance or progression. METHODS: Working memory and sustained attention tasks were presented to 158 female adolescents who were rated on dichotomous (body mass index percentile <85 vs. ≥85) and continuous (triceps skinfold thickness) measures of adiposity. RESULTS: The results revealed a significant association between excess adiposity and performance errors during the working memory task. During the sustained attention task, overweight/obese adolescents exhibited more EEG frontal beta power as well as greater intraindividual variability in reaction time and beta power across task periods than their normal-weight peers. Secondary analyses showed that frontal beta power during the sustained attention task was positively correlated with anxiety, panic, borderline personality features, drug abuse, and loss of control over food intake. CONCLUSIONS: The findings suggest that working memory and sustained attention decrements do exist among overweight/obese adolescent girls. The reliable detection of the decrements may depend on the difficulty of the tasks as well as the manner in which performance and brain activity are measured. Future studies should examine the relevance of these decrements to dietary education efforts and treatment response.

Visual illusions and inattention: Their association with adiposity among adolescent girls.

The Delboeuf concentric circle illusion is frequently invoked as an explanation for the hypothesized association between dinner plate size and overeating. We examined its association with adiposity among 162 girls, aged 14-18 years. We also examined the association of adiposity with neural and behavioral responses during a separate visual discrimination task. The analysis showed that girls with a body mass index percentile ≥ 85, or with greater triceps skinfold thickness, exhibited less sensitivity to the Delboeuf illusion than girls with normal adiposity. The excess adiposity group also exhibited significantly smaller electroencephalographic responses and more errors during the separate visual discrimination task. In combination, the findings from the two tasks suggest that girls with an elevated body mass are less sensitive to visual cues in their environment. The implications of these findings for weight loss education should be considered.

On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis.

BACKGROUND: As the architecture of complex traits incorporates a widening spectrum of genetic variation, analyses integrating common and rare variation are needed. Body mass index (BMI) represents a model trait, since common variation shows robust association but accounts for a fraction of the heritability. A combined analysis of single nucleotide polymorphisms (SNP) and copy number variation (CNV) was performed using 1850 European and 498 African-Americans from the Study of Addiction: Genetics and Environment. Genetic risk sum scores (GRSS) were constructed using 32 BMI-validated SNPs and aggregate-risk methods were compared: count versus weighted and proxy versus imputation. RESULTS: The weighted SNP-GRSS constructed from imputed probabilities of risk alleles performed best and was highly associated with BMI (p=4.3×10(-16)) accounting for 3% of the phenotypic variance. In addition to BMI-validated SNPs, common and rare BMI/obesity-associated CNVs were identified from the literature. Of the 84 CNVs previously reported, only 21-kilobase deletions on 16p12.3 showed evidence for association with BMI (p=0.003, frequency=16.9%), with two CNVs nominally associated with class II obesity, 1p36.1 duplications (OR=3.1, p=0.009, frequency 1.2%) and 5q13.2 deletions (OR=1.5, p=0.048, frequency 7.7%). All other CNVs, individually and in aggregate, were not associated with BMI or obesity. The combined model, including covariates, SNP-GRSS, and 16p12.3 deletion accounted for 11.5% of phenotypic variance in BMI (3.2% from genetic effects). Models significantly predicted obesity classification with maximum discriminative ability for morbid-obesity (p=3.15×10(-18)). CONCLUSION: Results show that incorporating validated effect sizes and allelic probabilities improve prediction algorithms. Although rare-CNVs did not account for significant phenotypic variation, results provide a framework for integrated analyses.

Who gains? Genetic and neurophysiological correlates of BMI gain upon college entry in women.

The present investigation examined P3 event-related electroencephalographic potentials and a short and selected list of addiction-related candidate gene single nucleotide polymorphisms (SNPs) within 84 female students, aged 18-20 yrs. The students were assigned to groups defined by the presence versus absence of a positive body mass index (BMI) change from the pre-college physical exam to the current day. Analyses revealed significantly greater P3 latencies and reduced P3 amplitudes during a response inhibition task among students who exhibited a BMI gain. BMI gain was also significantly associated with a ANKK1 SNP previously implicated in substance dependence risk. In logistic regression analyses, P3 latencies at the frontal electrode and this ANKK1 genotype correctly classified 71.1% of the students into the BMI groups. The present findings suggest that heritable indicators of impaired response inhibition can differentiate students who may be on a path toward an overweight or obese body mass.

Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with alcohol dependence.

Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder (AUD), despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; 17% Admixed African American ancestries; mean age: 38). We 1) conducted a genome-wide association study (GWAS) of SA and performed downstream analyses to determine whether we could identify specific biological pathways of risk, and 2) explored risk in aggregate across other clinical conditions, polygenic scores (PGS) for comorbid psychiatric problems, and neurocognitive functioning between those with AD who have and have not reported a lifetime suicide attempt. The GWAS and downstream analyses did not produce any significant associations. Participants with an AUD who had attempted suicide had greater rates of trauma exposure, major depressive disorder, post-traumatic stress disorder, and other substance use disorders compared to those who had not attempted suicide. Polygenic scores for suicide attempt, depression, and PTSD were associated with reporting a suicide attempt (ORs = 1.22-1.44). Participants who reported a SA also had decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences relative to those who did not, but differences were small. Overall, individuals with alcohol dependence who report SA appear to experience a variety of severe comorbidities and elevated polygenic risk for SA. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.

Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults.

Discrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12-25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.

Predicting Alcohol-Related Memory Problems in Older Adults: A Machine Learning Study with Multi-Domain Features.

Memory problems are common among older adults with a history of alcohol use disorder (AUD). Employing a machine learning framework, the current study investigates the use of multi-domain features to classify individuals with and without alcohol-induced memory problems. A group of 94 individuals (ages 50-81 years) with alcohol-induced memory problems (the memory group) were compared with a matched control group who did not have memory problems. The random forests model identified specific features from each domain that contributed to the classification of the memory group vs. the control group (AUC = 88.29%). Specifically, individuals from the memory group manifested a predominant pattern of hyperconnectivity across the default mode network regions except for some connections involving the anterior cingulate cortex, which were predominantly hypoconnected. Other significant contributing features were: (i) polygenic risk scores for AUD, (ii) alcohol consumption and related health consequences during the past five years, such as health problems, past negative experiences, withdrawal symptoms, and the largest number of drinks in a day during the past twelve months, and (iii) elevated neuroticism and increased harm avoidance, and fewer positive "uplift" life events. At the neural systems level, hyperconnectivity across the default mode network regions, including the connections across the hippocampal hub regions, in individuals with memory problems may indicate dysregulation in neural information processing. Overall, the study outlines the importance of utilizing multidomain features, consisting of resting-state brain connectivity data collected ~18 years ago, together with personality, life experiences, polygenic risk, and alcohol consumption and related consequences, to predict the alcohol-related memory problems that arise in later life.

Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with alcohol dependence.

Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder, despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; 17% Admixed African American ancestries; mean age: 38). We 1) explored clinical risk factors associated with SA, 2) conducted a genome-wide association study of SA, 3) examined whether individuals with a SA had elevated polygenic scores for comorbid psychiatric conditions (e.g., alcohol use disorders, lifetime suicide attempt, and depression), and 4) explored differences in electroencephalogram neural functional connectivity between those with and without a SA. One gene-based finding emerged, RFX3 (Regulatory Factor X, located on 9p24.2) which had supporting evidence in prior research of SA among individuals with major depression. Only the polygenic score for suicide attempts was associated with reporting a suicide attempt (OR = 1.20, 95% CI = 1.06, 1.37). Lastly, we observed decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences among those participants who reported a SA relative to those who did not, but differences were small. Overall, individuals with alcohol dependence who report SA appear to experience a variety of severe comorbidities and elevated polygenic risk for SA. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.

GABRA2 genotype, impulsivity, and body mass.

BACKGROUND: The goal of this study was to test a hypothesis associating impulsivity with an elevated body mass index (BMI). METHODS: To this end, we examined associations of BMI with putative genetic, neurophysiological, psychiatric, and psychological indicators of impulsivity in 78 women and 74 men formerly dependent on alcohol or drugs. A second analysis was designed to test the replicability of the genetic findings in an independent sample of 109 women and 111 men with a similar history of substance dependence. RESULTS: The results of the first analysis showed that BMI was positively correlated with Total and Nonplanning Scale Scores on the Barratt Impulsiveness Scale and the number of childhood symptoms of Attention-Deficit/Hyperactivity Disorder in women. It was also positively correlated, in women, with a GABRA2 variant previously implicated as a risk factor for substance dependence and an objective electroencephalographic feature previously associated with GABRA2 and relapse risk. The second analysis confirmed that the correlation between BMI and the substance-dependence-associated GABRA2 genotype was reliable and sex-specific. CONCLUSIONS: We conclude that an elevated BMI is associated with genetic, neurophysiological, psychiatric, and psychological indicators of impulsivity. The sex difference may be explained by greater opportunities to eat and overeat, a preference for higher calorie foods, a longer duration of alcohol/drug abstinence, or previous pregnancies in women.

Inter-trial variability in postural control and brain activation: Effects of previous opiate abuse.

There is an abundant literature demonstrating the superiority of inter-trial variability (ITV) of reaction time over mean reaction time in the early identification of subtle cognitive processing decrements. The present study extends these ideas by examining brain activation and postural control ITV among participants with versus without a history of chronic opiate abuse. Participants enrolled in opiate abuse (n = 82) and control (n = 112) groups completed tasks that challenged selective attention and balance. During the respective tasks, the inter-trial variabilities in frontal P300a electroencephalographic responses and sway strategy scores outperformed their mean levels in differentiating the groups. The relevance of several potential alternative explanations for the differences, including premorbid conduct disorder and comorbid alcohol abuse, depression, and methadone use, was discounted via simultaneous or post hoc analyses. It appears that chronic opiate abuse has adverse CNS effects that persist into the protracted abstinence period. These effects alter the temporal stability of its response to external and internal stimuli.