Now showing items 1-20 of 794

    • Regulation of PTP1B Activity and Insulin Resistance by Cellular Cholesterol

      Sagabala, Reddy Sudheer (2022-08)
      Protein Tyrosine phosphatase 1B (PTP1B), is an endoplasmic resident protein and a well-known negative regulator of the insulin receptor, dephosphorylating Tyr-1162, and Tyr-1163, two residues located in the activation loop of the insulin receptor. Mice lacking the PTPN1 gene encoding for PTP1B exhibit increased insulin sensitivity and improved glucose tolerance. Apart from its role in insulin signaling, mice lacking PTP1B show resistance to weight gain on a highfat diet, increased basal metabolic rate, and decreased cholesterol levels. In addition, PTP1B was previously identified in a proteome-wide mapping of cholesterol-interacting proteins in mammalian cells. However, the relationship between PTP1B and cholesterol is still unclear. To better understand the role of cholesterol on PTP1B function and on insulin signaling, we first used an in silico approach to predict cholesterol-binding sites in the 3D structure of the phosphatase and confirmed the binding sites through fluorescence binding studies and mass fingerprinting. We confirmed that the association between PTP1B and cholesterol occurred in both in vitro and in mammalian cells. In an attempt to understand whether cholesterol affects the ability of PTP1B to dephosphorylate substrates, we performed activity assays in various conditions. We observed that cholesterol could reduce and reactivate the reversibly oxidized form of PTP1B in vitro. Treatment of mammalian cells with cholesterol confirmed that excess cholesterol kept PTP1B reduced, and decreased Insulin Receptor phosphorylation and downstream signaling. In vivo results obtained by exposing mice to a high cholesterol diet support a role in the cholesterol-mediated reduction of PTP1B and decreased insulin sensitivity in the liver. We have established an electron tunneling path between the allosteric site and the catalytic cysteine residue and used a redox-sensitive fluorophore to measure electron tunneling in vitro. Hence, our results demonstrate for the first time that cholesterol binds to PTP1B at an allosteric site and reduces the phosphatase to regulate its activity and insulin signaling. Based on these results we propose a novel role for cholesterol in activating enzymes and in the context of insulin resistance.
    • The dynamic role of the androgen receptor (AR) and ABL interactor-1 (ABI1) axis in prostate cancer

      Kotula, Leszek; Porter, Baylee (2022-12)
      The nuclear hormone receptor and transcription factor, the androgen receptor (AR), is the main driver of prostate cancer growth and disease progression. Hallmark target genes of AR are used as biomarkers to indicate disease progression and treatment response. Furthermore, current clinical treatments for prostate cancer include androgen deprivation treatment and anti-AR which deplete ligand availability or directly target the androgen receptor, respectively. Transcription regulates key functions of living organisms in normal and diseases states, including cell growth and development, embryonic and adult tissue organization, and tumor progression. Here we identify a novel mechanism of transcriptional regulation by an actin regulatory and signaling protein, ABI1. As established by ChIP sequencing and DNA binding assays, ABI1 binds to chromatin through its intrinsically disordered DNA binding domain. Furthermore, ABI1 interacts with AR in vitro and in vivo and targets its activity to specific subset of genes. ABI1-AR driven transcription is dysregulated during prostate tumor progression. Additionally, anti-androgen and anti-AR treatments induce alterations in AR-mediated transcription which leads to downregulation of ABI1 expression and induces disruption of epithelial integrity. The results from this study indicate that ABI1 controls tumor plasticity through connecting actin cytoskeleton and cellular signaling to transcriptional regulation. We propose that ABI1 is a regulator of transcriptional homeostasis in prostate cancer.
    • Digital Eye Strain and Repeated Clinical Testing

      Chen, Tiffany Ying-Hsuan (2022-12)
      "Purpose: The use of digital devices has increased substantially over the past decades across all age groups for educational, career and leisure purposes. Although a high prevalence of Digital Eye Strain (DES) has been well established, especially during the recent pandemic, little is known about the association between repeated clinical testing and DES symptoms. The aim of this study was to determine whether symptoms of DES are associated with repeated measurements of standard clinical near-vision tests. Method: The study was performed on 30 young, normally-sighted individuals. Each participant completed 3 sessions to test accommodation (monocular facility, push-up amplitude), vergence (near point of convergence (NPC), near heterophoria) and accommodative-vergence interaction (AC/A ratio, binocular accommodative facility). Participants performed a cognitively demanding reading task from a tablet computer positioned at 33cm for 20 minutes. Repeated clinical measurements (3 readings) were taken both before and immediately after the reading task. Additionally, subjects completed a questionnaire regarding ocular and visual symptoms prior to and immediately after the reading period. Results: While a statistically significant difference in pre- and post-task DES symptom scores was observed (p < 0.01), no significant task-induced change in accommodation, vergence and accommodative-vergence measurements were found. Furthermore, there was no significant difference between the three consecutive readings for any of the pre- or post-task clinical parameters. Conclusion: These results indicate that repeated measurements of standard clinical near-vision tests are not associated with Digital Eye Strain (DES) symptoms. Additionally, no significant difference between the three repeated pre- or post-task measurements was found. "
    • Effect of Implementation Facilitation to Promote Adoption of Medications for Addiction Treatment in US HIV Clinics: A Randomized Clinical Trial.

      Edelman, E Jennifer; Gan, Geliang; Dziura, James; Esserman, Denise; Porter, Elizabeth; Becker, William C; Chan, Philip A; Cornman, Deborah H; Helfrich, Christian D; Reynolds, Jesse; et al. (2022-10-03)
      Importance: Medications for addiction treatment (MAT) are inconsistently offered in HIV clinics. Objective: To evaluate the impact of implementation facilitation (hereafter referred to as "facilitation"), a multicomponent implementation strategy, on increasing provision of MAT for opioid use disorder (MOUD), alcohol use disorder (MAUD), and tobacco use disorder (MTUD). Design, setting, and participants: Conducted from July 26, 2016, through July 25, 2020, the Working with HIV Clinics to adopt Addiction Treatment using Implementation Facilitation (WHAT-IF?) study used an unblinded, stepped wedge design to sequentially assign each of 4 HIV clinics in the northeastern US to cross over from control (ie, baseline practices) to facilitation (ie, intervention) and then evaluation and maintenance periods every 6 months. Participants were adult patients with opioid, alcohol, or tobacco use disorder. Data analysis was performed from August 2020 to September 2022. Interventions: Multicomponent facilitation. Main outcomes and measures: Outcomes, assessed using electronic health record data, were provision of MAT among patients with opioid, alcohol, or tobacco use disorder during the evaluation (primary outcome) and maintenance periods compared with the control period. Results: Among 3647 patients, the mean (SD) age was 49 (12) years, 1814 (50%) were Black, 781 (22%) were Hispanic, and 1407 (39%) were female; 121 (3%) had opioid use disorder, 126 (3%) had alcohol use disorder, and 420 (12%) had tobacco use disorder. Compared with the control period, there was no increase in provision of MOUD with facilitation during the evaluation period (243 patients [27%; 95% CI, 22%-32%] vs 135 patients [28%; 95% CI, 22%-35%]; P = .59) or maintenance period (198 patients [29%; 95% CI, 22%-36%]; P = .48). The change in provision of MAUD from the control period to the evaluation period was not statistically significant (251 patients [8%; 95% CI, 5%-12%] vs 112 patients [13%; 95% CI, 8%-21%]; P = .11); however, the difference increased and became significant during the maintenance period (180 patients [17%; 95% CI, 12%-24%]; P = .009). There were significant increases in provision of MTUD with facilitation during both the evaluation (810 patients [33%; 95% CI, 30%-36%] vs 471 patients [40%; 95% CI, 36%-45%]; P = .005) and maintenance (643 patients [38%; 95% CI, 34%-41%]; P = .047) periods. Conclusions and relevance: In this randomized clinical trial, facilitation led to increased provision of MTUD, delayed improvements in MAUD, and no improvements in MOUD in HIV clinics. Enhanced strategies, potentially including clinic and patient incentives, especially for MOUD, may be needed to further increase provision of MAT in HIV clinics. Trial registration: ClinicalTrials.gov Identifier: NCT02907944.
    • Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples.

      Johnson, Emma C; Sanchez-Roige, Sandra; Acion, Laura; Adams, Mark J; Bucholz, Kathleen K; Chan, Grace; Chao, Michael J; Chorlian, David B; Dick, Danielle M; Edenberg, Howard J; et al. (2020-01-20)
      Background: Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds. Methods: We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes. Results: In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16). Conclusions: AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
    • Item-Level Genome-Wide Association Study of the Alcohol Use Disorders Identification Test in Three Population-Based Cohorts.

      Mallard, Travis T; Savage, Jeanne E; Johnson, Emma C; Huang, Yuye; Edwards, Alexis C; Hottenga, Jouke J; Grotzinger, Andrew D; Gustavson, Daniel E; Jennings, Mariela V; Anokhin, Andrey; et al. (2021-05-14)
      Objective: Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT. Methods: To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases. Results: The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health. Conclusions: This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.
    • Genome-wide association studies of the self-rating of effects of ethanol (SRE).

      Lai, Dongbing; Wetherill, Leah; Kapoor, Manav; Johnson, Emma C; Schwandt, Melanie; Ramchandani, Vijay A; Goldman, David; Joslyn, Geoff; Rao, Xi; Liu, Yunlong; et al. (2019-07-03)
      The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (r : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.
    • Genome-wide admixture mapping of DSM-IV alcohol dependence, criterion count, and the self-rating of the effects of ethanol in African American populations.

      Lai, Dongbing; Kapoor, Manav; Wetherill, Leah; Schwandt, Melanie; Ramchandani, Vijay A; Goldman, David; Chao, Michael; Almasy, Laura; Bucholz, Kathleen; Hart, Ronald P; et al. (2020-07-11)
      African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome-wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM-IV alcohol dependence diagnosis, DSM-IV alcohol dependence criterion count, and two scores from the self-rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE-5) and average of SRE across three times (SRE-T). Findings revealed a region on chromosome 4 that was genome-wide significant for SRE-5 (p value = 4.18E-05). Fine mapping did not identify a single causal variant to be associated with SRE-5; instead, conditional analysis concluded that multiple variants collectively explained the admixture mapping signal. PPARGC1A, a gene that has been linked to alcohol consumption in previous studies, is located in this region. Our finding suggests that admixture mapping is a useful tool to identify genes/variants that may have been missed by current GWAS approaches in admixed populations.
    • Alcohol-Related, Drug-Related, and Non-Substance-Related Aggression: 3 Facets of a Single Construct or 3 Distinct Constructs?

      Chester, David S; Bucholz, Kathleen K; Chan, Grace; Kamarajan, Chella; Pandey, Ashwini K; Wetherill, Leah; Kramer, John R; Nurnberger, John I; Salvatore, Jessica E; Dick, Danielle M (2020-08-06)
      Background: Aggression often occurs alongside alcohol and drug misuse. However, it is not clear whether the latent and manifest relations among alcohol-related, drug-related, and non-substance-related aggression are separate manifestations of a single construct or instead are 3 distinct constructs. Methods: To examine these associations, we conducted a preregistered analysis of 13,490 participants in the Collaborative Study on the Genetics of Alcoholism. In a structured interview, participants reported their lifetime perpetration of these 3 aggression phenotypes. Results: The data were better fit by a model that treated these aggression phenotypes as 3 distinct latent factors, as compared to models in which the items all loaded onto 1 ("general") or 2 ("substance-related" and "non-substance-related") aggression factors. This 3-factor model fit better for men than women. Subsequent exploratory analyses then showed that among these 3 factors, alcohol-related aggression explained the variance of overall aggression better than the other 2 factors. Conclusions: Our findings suggest that these 3 forms of aggression are distinct phenotypes (especially among men). Yet, people's alcohol-related aggression can accurately characterize their overall aggressive tendencies across these domains. Future research will benefit from articulating the unique and shared pathways and risk factors underlying each of these facets of aggression.
    • Characterization of Service Use for Alcohol Problems Across Generations and Sex in Adults With Alcohol Use Disorder.

      Bourdon, Jessica L; Tillman, Rebecca; Francis, Meredith W; Dick, Danielle M; Stephenson, Mallory; Kamarajan, Chella; Edenberg, Howard J; Kramer, John; Kuperman, Samuel; Bucholz, Kathleen K; et al. (2020-02-13)
      Background: There are gaps in the literature on service use (help-seeking and treatment utilization) for alcohol problems among those with alcohol use disorder (AUD). First, policy changes and cultural shifts (e.g., insurance) related to AUD have occurred over the last few decades, making it important to study generational differences. Second, multiple studies have found that females receive fewer services than males, and exploring whether these sex differences persist across generations can inform public health and research endeavors. The current study examined service use for alcohol problems among individuals with AUD. The aims were as follows: (i) to describe service use for alcohol problems; (ii) to assess generational differences (silent [b. 1928 to 1945], boomer [b. 1946 to 1964], generation X [b. 1965 to 1980], millennial [b. 1981 to 1996]) in help-seeking and treatment utilization; and (iii) to examine sex differences across generations. Methods: Data were from affected family members of probands who participated in the Collaborative Study on the Genetics of Alcoholism (N = 4,405). First, frequencies for service use variables were calculated across generations. Pearson chi-square and ANOVA were used to test for differences in rates and types of service use across generations, taking familial clustering into account. Next, Cox survival modeling was used to assess associations of generation and sex with time to first help-seeking and first treatment for AUD, and time from first onset of AUD to first help-seeking and first treatment. Interactions between generation and sex were tested within each Cox regression. Results: Significant hazards were found in all 4 transitions. Overall, younger generations used services earlier than older generations, which translated into higher likelihoods of these behaviors. Regardless of generation, younger females were less likely to use services than males. Conclusions: There are generational and sex differences in service use for alcohol problems among individuals with AUD. Policy and clinical implications are discussed.
    • Pathways to post-traumatic stress disorder and alcohol dependence: Trauma, executive functioning, and family history of alcoholism in adolescents and young adults.

      Subbie-Saenz de Viteri, Stacey; Pandey, Ashwini; Pandey, Gayathri; Kamarajan, Chella; Smith, Rebecca; Anokhin, Andrey; Bauer, Lance; Bender, Annah; Chan, Grace; Dick, Danielle; et al. (2020-09-29)
      Introduction: Family history (FH) of alcohol dependence is likely to increase the risk of trauma exposure, post-traumatic stress disorder (PTSD), and alcohol dependence. FH of alcohol dependence and trauma has been separately shown to adversely affect planning/problem-solving aspects of executive function. However, few studies have examined these risk factors in an integrated model. Methods: Using data from trauma-exposed individuals from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1,860), comprising offspring from alcohol-dependent high-risk and comparison families (mean age [SE] = 21.9 [4.2]), we investigated associations of trauma (nonsexual assaultive, nonassaultive, sexual assaultive) with DSM-IV PTSD and alcohol dependence symptom counts, and planning/problem-solving abilities assessed using the Tower of London Test (TOLT). Moderating effects of family history density of alcohol use disorder (FHD) on these associations and sex differences were explored. Results: Family history density was positively associated with PTSD in female participants who endorsed a sexual assaultive trauma. Exposure to nonsexual assaultive trauma was associated with more excess moves made on the TOLT. Conclusion: Findings from this study demonstrate associations with PTSD and alcohol dependence symptom counts, as well as poor problem-solving ability in trauma-exposed individuals from families densely affected with alcohol dependence, depending on trauma type, FHD, and sex. This suggests that having a FH of alcohol dependence and exposure to trauma during adolescence may be associated with more PTSD and alcohol dependence symptoms, and poor problem-solving abilities in adulthood.
    • 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.

      Pandey, Gayathri; Seay, Michael J; Meyers, Jacquelyn L; Chorlian, David B; Pandey, Ashwini K; Kamarajan, Chella; Ehrenberg, Morton; Pitti, Daniel; Kinreich, Sivan; Subbie-Saenz de Viteri, Stacey; et al. (2020-02-18)
      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.
    • A genome-wide association study of interhemispheric theta EEG coherence: implications for neural connectivity and alcohol use behavior.

      Meyers, Jacquelyn L; Zhang, Jian; Chorlian, David B; Pandey, Ashwini K; Kamarajan, Chella; Wang, Jen-Chyong; Wetherill, Leah; Lai, Dongbing; Chao, Michael; Chan, Grace; et al. (2020-05-20)
      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). 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.
    • Random Forest Classification of Alcohol Use Disorder Using fMRI Functional Connectivity, Neuropsychological Functioning, and Impulsivity Measures.

      Kamarajan, Chella; Ardekani, Babak A; Pandey, Ashwini K; Kinreich, Sivan; Pandey, Gayathri; Chorlian, David B; Meyers, Jacquelyn L; Zhang, Jian; Bermudez, Elaine; Stimus, Arthur T; et al. (2020-02-20)
      Individuals with alcohol use disorder (AUD) are known to manifest a variety of neurocognitive impairments that can be attributed to alterations in specific brain networks. The current study aims to identify specific features of brain connectivity, neuropsychological performance, and impulsivity traits that can classify adult males with AUD ( = 30) from healthy controls (CTL, = 30) using the Random Forest (RF) classification method. The predictor variables were: (i) fMRI-based within-network functional connectivity (FC) of the Default Mode Network (DMN), (ii) neuropsychological scores from the Tower of London Test (TOLT), and the Visual Span Test (VST), and (iii) impulsivity factors from the Barratt Impulsiveness Scale (BIS). The RF model, with a classification accuracy of 76.67%, identified fourteen DMN connections, two neuropsychological variables (memory span and total correct scores of the forward condition of the VST), and all impulsivity factors as significantly important for classifying participants into either the AUD or CTL group. Specifically, the AUD group manifested hyperconnectivity across the bilateral anterior cingulate cortex and the prefrontal cortex as well as between the bilateral posterior cingulate cortex and the left inferior parietal lobule, while showing hypoconnectivity in long-range anterior-posterior and interhemispheric long-range connections. Individuals with AUD also showed poorer memory performance and increased impulsivity compared to CTL individuals. Furthermore, there were significant associations among FC, impulsivity, neuropsychological performance, and AUD status. These results confirm the previous findings that alterations in specific brain networks coupled with poor neuropsychological functioning and heightened impulsivity may characterize individuals with AUD, who can be efficiently identified using classification algorithms such as Random Forest.
    • Random Forest Classification of Alcohol Use Disorder Using EEG Source Functional Connectivity, Neuropsychological Functioning, and Impulsivity Measures.

      Kamarajan, Chella; Ardekani, Babak A; Pandey, Ashwini K; Chorlian, David B; Kinreich, Sivan; Pandey, Gayathri; Meyers, Jacquelyn L; Zhang, Jian; Kuang, Weipeng; Stimus, Arthur T; et al. (2020-03-01)
      Individuals with alcohol use disorder (AUD) manifest a variety of impairments that can be attributed to alterations in specific brain networks. The current study aims to identify features of EEG-based functional connectivity, neuropsychological performance, and impulsivity that can classify individuals with AUD (N = 30) from unaffected controls (CTL, N = 30) using random forest classification. The features included were: (i) EEG source functional connectivity (FC) of the default mode network (DMN) derived using eLORETA algorithm, (ii) neuropsychological scores from the Tower of London test (TOLT) and the visual span test (VST), and (iii) impulsivity factors from the Barratt impulsiveness scale (BIS). The random forest model achieved a classification accuracy of 80% and identified 29 FC connections (among 66 connections per frequency band), 3 neuropsychological variables from VST (total number of correctly performed trials in forward and backward sequences and average time for correct trials in forward sequence) and all four impulsivity scores (motor, non-planning, attentional, and total) as significantly contributing to classifying individuals as either AUD or CTL. Although there was a significant age difference between the groups, most of the top variables that contributed to the classification were not significantly correlated with age. The AUD group showed a predominant pattern of hyperconnectivity among 25 of 29 significant connections, indicating aberrant network functioning during resting state suggestive of neural hyperexcitability and impulsivity. Further, parahippocampal hyperconnectivity with other DMN regions was identified as a major hub region dysregulated in AUD (13 connections overall), possibly due to neural damage from chronic drinking, which may give rise to cognitive impairments, including memory deficits and blackouts. Furthermore, hypoconnectivity observed in four connections (prefrontal nodes connecting posterior right-hemispheric regions) may indicate a weaker or fractured prefrontal connectivity with other regions, which may be related to impaired higher cognitive functions. The AUD group also showed poorer memory performance on the VST task and increased impulsivity in all factors compared to controls. Features from all three domains had significant associations with one another. These results indicate that dysregulated neural connectivity across the DMN regions, especially relating to hyperconnected parahippocampal hub as well as hypoconnected prefrontal hub, may potentially represent neurophysiological biomarkers of AUD, while poor visual memory performance and heightened impulsivity may serve as cognitive-behavioral indices of AUD.
    • High Polygenic Risk Scores Are Associated With Early Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk.

      Nurnberger, John I; Wang, Yumin; Zang, Yong; Lai, Dongbing; Wetherill, Leah; Edenberg, Howard J; Aliev, Fazil; Plawecki, Martin H; Chorlian, David; Chan, Grace; et al. (2021-11-01)
      Background: Genome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations. Methods: A total of 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism were followed, with clinical assessments every 2 years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry and African ancestry. Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using receiver operating characteristic curves and by analysis of the distribution of PRS. Results: European ancestry subjects with higher than median PRSs were at greater risk for onset of AUD than subjects with lower than median PRSs (p = 3 × 10-7). Area under the curve for the receiver operating characteristic analysis peaked at 0.88 to 0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high-risk sample, European ancestry subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared with risks of 54% and 16%, respectively, in the lowest quartile). Conclusions: Predictive power for PRSs in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application.
    • Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases.

      Kapoor, Manav; Chao, Michael J; Johnson, Emma C; Novikova, Gloriia; Lai, Dongbing; Meyers, Jacquelyn L; Schulman, Jessica; Nurnberger, John I; Porjesz, Bernice; Liu, Yunlong; et al. (2021-08-20)
      Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.
    • Associations between Suicidal Thoughts and Behaviors and Genetic Liability for Cognitive Performance, Depression, and Risk-Taking in a High-Risk Sample.

      Johnson, Emma C; Aliev, Fazil; Meyers, Jacquelyn L; Salvatore, Jessica E; Tillman, Rebecca; Chang, Yoonhoo; Docherty, Anna R; Bogdan, Ryan; Acion, Laura; Chan, Grace; et al. (2021-05-18)
      Background: Suicidal thoughts and behaviors (STBs) and nonsuicidal self-injury (NSSI) behaviors are moderately heritable and may reflect an underlying predisposition to depression, impulsivity, and cognitive vulnerabilities to varying degrees. Objectives: We aimed to estimate the degrees of association between genetic liability to depression, impulsivity, and cognitive performance and STBs and NSSI in a high-risk sample. Methods: We used data on 7,482 individuals of European ancestry and 3,359 individuals of African ancestry from the Collaborative Study on the Genetics of Alcoholism to examine the links between polygenic scores (PGSs) for depression, impulsivity/risk-taking, and cognitive performance with 3 self-reported indices of STBs (suicidal ideation, persistent suicidal ideation defined as ideation occurring on at least 7 consecutive days, and suicide attempt) and with NSSI. Results: The PGS for depression was significantly associated with all 4 primary self-harm measures, explaining 0.6-2.5% of the variance. The PGS for risk-taking behaviors was also associated with all 4 self-harm behaviors in baseline models, but was no longer associated after controlling for a lifetime measure of DSM-IV alcohol dependence and abuse symptom counts. Polygenic predisposition for cognitive performance was negatively associated with suicide attempts (q = 3.8e-4) but was not significantly associated with suicidal ideation nor NSSI. We did not find any significant associations in the African ancestry subset, likely due to smaller sample sizes. Conclusions: Our results encourage the study of STB as transdiagnostic outcomes that show genetic overlap with a range of risk factors.
    • Parameters of Spinal Cord Stimulation in Complex Regional Pain Syndrome: Systematic Review and Meta-analysis of Randomized Controlled Trials.

      Ho, Elver; Yazdanpanah, Nima; Ho, Johnson; Drukman, Benjamin; Chang, Alvin; Agarwal, Sanjeev
      Background: Complex Regional Pain Syndrome (CRPS) is a chronic debilitating neuropathic pain condition characterized by autonomic and inflammatory features that typically occurs after a traumatic event. Spinal cord stimulation (SCS) has been shown to be effective in the treatment of chronic CRPS refractory to conventional treatment modalities. The collective evidence of novel parameters of SCS for treating CRPS has not been characterized extensively. Objective: To provide evidence for the use of SCS to treat CRPS and characterize the additional benefits of various SCS waveforms. Study design: Systematic Review and Meta-analysis. Methods: PubMed, Embase and CINHLA were screened for all randomized controlled trials (RCT) comparing SCS parameters for the treatment of CRPS. Results: Four RCTs were identified that included SCS as a treatment arm for CRPS. Of these, one study compared low frequency tonic SCS (LF-SCS) versus conventional physical therapy, 2 studies compared placebo/sham SCS with LF-SCS and a multitude of waveforms, and one study compared LF-SCS with high-frequency SCS (HF-SCS). Two of the studies were rated as having a low risk of bias, one study was rated as having some concerns for bias, while the final study was rated as having a high risk of bias. A meta-analysis of 4 studies comparing conventional therapy/placebo SCS stimulation against LF-SCS revealed increased benefit of LF-SCS in pain reduction up to a month (mean difference [MD] = -1.17 points; 95% CI = -1.61 to -0.73; P < 0.001, I2 = 42%). Another meta-analysis of 2 studies showed that LF-SCS results in higher global perceived effect scores relative to conventional therapy/placebo SCS stimulation (MD = 1.58; 95% CI = 1.00 to 2.15; P < 0.001, I2 = 0%). Limitations: A pooled analysis using different designs for RCTs was conducted. Some studies folded in multiple neuropathic pain pathologies in addition to CRPS. One study was at a high risk for bias in at least one domain. Conclusion: LF-SCS is superior to conventional therapy/placebo SCS stimulation. However, more evidence is required to demonstrate that novel SCS parameters are superior to LF-SCS in improving pain scores and functional outcomes.
    • Lymphocytic Esophagitis: Diagnosis and Management in the Emergency Department vs Initial Suspicion of Eosinophilic Esophagitis.

      Banks, Wesley D; Cassar, Christian; Cassar, Philip (2022-10-14)
      Lymphocytic esophagitis is an increasingly prevalent yet poorly understood condition that is highly disruptive to daily living. The presentation often includes dysphagia, but dysarthria and narrowing of the esophageal lumen may be seen as well. In this case, a 66-year-old female presented to the Emergency Department complaining of dysphagia for several weeks in addition to associated discomfort with the loss of ability to swallow solid foods.