Browsing by Author "Meyers, Jacquelyn L."
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Item Alcohol consumption mediates the relationship between ADH1B and DSM-IV alcohol use disorder and criteria(Alcohol Research Documentation, 2014-07) Kilcoyne, Bari; Shmulewitz, Dvora; Meyers, Jacquelyn L.; Aharonovich, Efrat; Greenstein, Eliana; Frisch, Amos; Weizman, Abraham; Spivak, Baruch; Edenberg, Howard J.; Gelertner, Joel; Hasin, Deborah S.; Department of Biochemistry and Molecular Biology, IU School of MedicineOBJECTIVE: A single nucleotide variation in the alcohol dehydrogenase 1B (ADH1B) gene, rs1229984, produces an ADH1B enzyme with faster acetaldehyde production. This protective variant is associated with lower alcohol consumption and lower risk for alcohol use disorders (AUDs). Based on the premise that faster ADH1B kinetics decreases alcohol consumption, we formally tested if the association between ADH1B variant rs1229984 and AUDs occurs through consumption. We also tested whether the association between rs1229984 and each of the 11 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), AUD criteria occurs through consumption. METHOD: A total of 1,130 lifetime drinkers from an Israeli household sample were assessed with a structured interview and genotyped for rs1229984 (protective allele frequency = 0.28). Logistic regression evaluated the association between rs1229984 and each phenotype (AUDs, 11 individual DSM-IV criteria). For phenotypes significantly related to rs1229984, the effect through consumption was tested with logistic regression and bootstrapping. RESULTS: ADH1B rs1229984 was significantly associated with AUDs and six criteria, with odds ratios ranging from 1.32 to 1.96. The effect through consumption was significant for these relationships, explaining 23%-74% of the total ADH1B effect. CONCLUSIONS: This is the first study to show that ADH1B rs1229984 is related to 6 of the 11 DSM-IV AUD criteria and that alcohol consumption explained a significant proportion of these associations and the association of ADH1B with AUDs. Better understanding of the relationship between ADH1B and the DSM-IV AUD criteria, including effects through consumption, will enhance our understanding of the etiologic model through which AUDs can occur.Item Alcohol metabolizing genes and alcohol phenotypes in an Israeli household sample(Wiley, 2013-11) Meyers, Jacquelyn L.; Shmulewitz, Dvora; Aharonovich, Efrat; Waxman, Rachel; Frisch, Amos; Weizman, Abraham; Spivak, Baruch; Edenberg, Howard J.; Gelernter, Joel; Hasin, Deborah; Biochemistry & Molecular Biology, School of MedicineBACKGROUND: Alcohol dehydrogenase 1B and 1C (ADH1B and ADH1C) variants have been robustly associated with alcohol phenotypes in East Asian populations, but less so in non-Asian populations where prevalence of the most protective ADH1B allele is low (generally <5%). Further, the joint effects of ADH1B and ADH1C on alcohol phenotypes have been unclear. Therefore, we tested the independent and joint effects of ADH1B and ADH1C on alcohol phenotypes in an Israeli sample, with higher prevalence of the most protective ADH1B allele than other non-Asian populations. METHODS: A structured interview assessed lifetime drinking and alcohol use disorders (AUDs) in adult Israeli household residents. Four single nucleotide polymorphisms (SNPs) were genotyped: ADH1B (rs1229984, rs1229982, and rs1159918) and ADH1C (rs698). Regression analysis examined the association between alcohol phenotypes and each SNP (absence vs. presence of the protective allele) as well as rs698/rs1229984 diplotypes (also indicating absence or presence of protective alleles) in lifetime drinkers (n = 1,129). RESULTS: Lack of the ADH1B rs1229984 protective allele was significantly associated with consumption- and AUD-related phenotypes (OR = 1.77 for AUD; OR = 1.83 for risk drinking), while lack of the ADH1C rs698 protective allele was significantly associated with AUD-related phenotypes (OR = 2.32 for AUD). Diplotype analysis indicated that jointly ADH1B and ADH1C significantly influenced AUD-related phenotypes. For example, among those without protective alleles for ADH1B or ADH1C, OR for AUD was 1.87 as compared to those without the protective allele for ADH1B only and was 3.16 as compared to those with protective alleles for both ADH1B and ADH1C. CONCLUSIONS: This study adds support for the relationship of ADH1B and ADH1C and alcohol phenotypes in non-Asians. Further, these findings help clarify the mixed results from previous studies by showing that ADH1B and ADH1C jointly effect AUDs, but not consumption. Studies of the association between alcohol phenotypes and either ADH1B or ADH1C alone may employ an oversimplified model, masking relevant information.Item Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism(Springer Nature, 2019-02-14) Kapoor, Manav; Wang, Jen-Chyong; Farris, Sean P.; Liu, Yunlong; McClintick, Jeanette; Gupta, Ishaan; Meyers, Jacquelyn L.; Bertelsen, Sarah; Chao, Michael; Nurnberger, John; Tischfield, Jay; Harari, Oscar; Zeran, Li; Hesselbrock, Victor; Bauer, Lance; Raj, Towfique; Porjesz, Bernice; Agrawal, Arpana; Foroud, Tatiana; Edenberg, Howard J.; Mayfield, R. Dayne; Goate, Alison; Medical and Molecular Genetics, School of MedicineAlcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank's alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.Item Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood(MDPI, 2019-10-17) Meyers, Jacquelyn L.; Chorlian, David B.; Johnson, Emma C.; Pandey, Ashwini K.; Kamarajan, Chella; Salvatore, Jessica E.; Aliev, Fazil; Subbie-Saenz de Viteri, Stacey; Zhang, Jian; Chao, Michael; Kapoor, Manav; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John; Tischfield, Jay; Goate, Alison; Foroud, Tatiana; Dick, Danielle M.; Edenberg, Howard J.; Agrawal, Arpana; Porjesz, Bernice; Medical and Molecular Genetics, School of MedicineDifferences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS (p-threshold < 0.001) was associated with increased fronto-central, tempo-parietal, centro-parietal, and parietal-occipital interhemispheric theta and alpha connectivity in males only from ages 18-31 (beta coefficients ranged from 0.02-0.06, p-values ranged from 10-6-10-12), but not in females. Individuals with higher AD PRS also demonstrated more performance deficits on neuropsychological tasks (Tower of London task, visual span test) as well as increased risk for lifetime DSM-5 alcohol and opioid use disorders. We conclude that measures of neural connectivity, together with neurocognitive performance and substance use behavior, can be used to further understanding of how genetic risk variants from large GWAS of AUD may influence brain function. In addition, these data indicate the importance of examining sex and developmental effects, which otherwise may be masked. Understanding of neural mechanisms linking genetic variants emerging from GWAS to risk for AUD throughout development may help to identify specific points when neurocognitive prevention and intervention efforts may be most effective.Item Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users(Oxford University Press, 2023) Johnson, Emma C.; Colbert, Sarah M. C.; Jeffries, Paul W.; Tillman, Rebecca; Bigdeli, Tim B.; Karcher, Nicole R.; Chan, Grace; Kuperman, Samuel; Meyers, Jacquelyn L.; Nurnberger, John I.; Plawecki, Martin H.; Degenhardt, Louisa; Martin, Nicholas G.; Kamarajan, Chella; Schuckit, Marc A.; Murray, Robin M.; Dick, Danielle M.; Edenberg, Howard J.; D'Souza, Deepak Cyril; Di Forti, Marta; Porjesz, Bernice; Nelson, Elliot C.; Agrawal, Arpana; Medical and Molecular Genetics, School of MedicineBackground and hypothesis: Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. Study design: We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD). Study results: Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample. Conclusions: Among individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use.Item Associations between Suicidal Thoughts and Behaviors and Genetic Liability for Cognitive Performance, Depression, and Risk-Taking in a High-Risk Sample(Karger, 2021) Johnson, Emma C.; Aliev, Fazil; Meyers, Jacquelyn L.; Salvatore, Jessica E.; Tillman, Rebecca; Chang, Yoonhoo; Docherty, Anna R.; Bogdan, Ryan; Acion, Laura; Chan, Grace; Chorlian, David B.; Kamarajan, Chella; Kuperman, Samuel; Pandey, Ashwini; Plawecki, Martin H.; Schuckit, Marc; Tischfield, Jay; Edenberg, Howard J.; Bucholz, Kathleen K.; Nurnberger, John I.; Porjesz, Bernice; Hesselbrock, Victor; Dick, Danielle M.; Kramer, John R.; Agrawal, Arpana; Psychiatry, School of MedicineBackground: 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.Item Associations of parent–adolescent closeness with P3 amplitude, frontal theta, and binge drinking among offspring with high risk for alcohol use disorder(Wiley, 2023) Pandey, Gayathri; Kuo, Sally I-Chun; Horne-Osipenko, Kristina A.; Pandey, Ashwini K.; Kamarajan, Chella; Saenz de Viteri, Stacey; Kinreich, Sivan; Chorlian, David B.; Kuang, Weipeng; Stephenson, Mallory; Kramer, John; Anokhin, Andrey; Zang, Yong; Kuperman, Samuel; Hesselbrock, Victor; Schuckit, Marc; Dick, Danielle; Chan, Grace; McCutcheon, Vivia V.; Edenberg, Howard; Bucholz, Kathleen K.; Meyers, Jacquelyn L.; Porjesz, Bernice; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground: Parents impact their offspring's brain development, neurocognitive function, risk, and resilience for alcohol use disorder (AUD) via both genetic and socio-environmental factors. Individuals with AUD and their unaffected children manifest low parietal P3 amplitude and low frontal theta (FT) power, reflecting heritable neurocognitive deficits associated with AUD. Likewise, children who experience poor parenting tend to have atypical brain development and greater rates of alcohol problems. Conversely, positive parenting can be protective and critical for normative development of self-regulation, neurocognitive functioning and the neurobiological systems subserving them. Yet, the role of positive parenting in resiliency toward AUD is understudied and its association with neurocognitive functioning and behavioral vulnerability to AUD among high-risk offspring is less known. Using data from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1256, mean age [SD] = 19.25 [1.88]), we investigated the associations of closeness with mother and father during adolescence with offspring P3 amplitude, FT power, and binge drinking among high-risk offspring. Methods: Self-reported closeness with mother and father between ages 12 and 17 and binge drinking were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. P3 amplitude and FT power were assessed in response to target stimuli using a Visual Oddball Task. Results: Multivariate multiple regression analyses showed that closeness with father was associated with larger P3 amplitude (p = 0.002) and higher FT power (p = 0.01). Closeness with mother was associated with less binge drinking (p = 0.003). Among male offspring, closeness with father was associated with larger P3 amplitude, but among female offspring, closeness with mother was associated with less binge drinking. These associations remained statistically significant with father's and mothers' AUD symptoms, socioeconomic status, and offspring impulsivity in the model. Conclusions: Among high-risk offspring, closeness with parents during adolescence may promote resilience for developing AUD and related neurocognitive deficits albeit with important sex differences.Item CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving(Rutgers Center of Alcohol Studies, 2016-03) Shmulewitz, Dvora; Meyers, Jacquelyn L.; Wall, Melanie M.; Aharonovich, Efrat; Frisch, Amos; Spivak, Baruch; Weizman, Abraham; Edenberg, Howard J.; Gelernter, Joel; Hasin, Deborah S.; Department of Biochemistry & Molecular Biology, IU School of MedicineOBJECTIVE: Nicotine craving is considered an important element in the persistence of cigarette smoking, but little is known about the role of craving in the widely recognized association between variants mapped to the neuronal nicotinic acetylcholine receptor (CHRN) genes on chromosome 15 and nicotine phenotypes. METHOD: The associations between CHRNA5-CHRNA3-CHRNB4 variants and cigarettes per day (CPD), the Fagerström Test for Nicotine Dependence (FTND), and craving were analyzed in data from 662 lifetime smokers from an Israeli adult Jewish household sample. Indirect effects of genotype on nicotine phenotypes through craving were formally tested using regression and bootstrapping procedures. RESULTS: At CHRNA3, allele G of rs3743078 was associated with increased craving, CPD, and FTND scores: Participants with one or two copies of the G allele had, on average, higher scores on the craving scale (p = .0025), more cigarettes smoked (p = .0057), and higher scores on the FTND (p =.0024). With craving in the model, variant rs3743078 showed a significant indirect effect through craving on CPD (p = .0026) and on FTND score (p = .0024). A sizeable proportion of the total rs3743078 effect on CPD (56.4%) and FTND (65.2%) was indirect through craving. CONCLUSIONS: These results suggest that nicotine craving may play a central role in nicotine use disorders and may have utility as a therapeutic target.Item Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts(Springer, 2022-10-04) Barr, Peter B.; Driver, Morgan N.; Kuo, Sally I-Chun; Stephenson, Mallory; Aliev, Fazil; Linnér, Richard Karlsson; Marks, Jesse; Anokhin, Andrey P.; Bucholz, Kathleen; Chan, Grace; Edenberg, Howard J.; Edwards, Alexis C.; Francis, Meredith W.; Hancock, Dana B.; Harden, K. Paige; Kamarajan, Chella; Kaprio, Jaakko; Kinreich, Sivan; Kramer, John R.; Kuperman, Samuel; Latvala, Antti; Meyers, Jacquelyn L.; Palmer, Abraham A.; Plawecki, Martin H.; Porjesz, Bernice; Rose, Richard J.; Schuckit, Marc A.; Salvatore, Jessica E.; Dick , Danielle M.; Medical and Molecular Genetics, School of MedicineSubstance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.Item Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with alcohol dependence(medRxiv, 2023-04-29) Barr, Peter B.; Neale, Zoe; Schulman, Jessica; Mullins, Niamh; Zhang, Jian; Chorlian, David B.; Kamarajan, Chella; Kinreich, Sivan; Pandey, Ashwini K.; Pandey, Gayathri; Saenz de Viteri, Stacey; Acion, Laura; Bauer, Lance; Bucholz, Kathleen K.; Chan, Grace; Chao, Michael; Dick, Danielle M.; Edenberg, Howard J.; Foroud, Tatiana; Goate, Alison; Hesselbrock, Victor; Johnson, Emma C.; Kramer, John; Lai, Dongbing; Plawecki, Martin H.; Salvatore, Jessica E.; Wetherill, Leah; Agrawal, Arpana; Porjesz, Bernice; Meyers, Jacquelyn L.; Medical and Molecular Genetics, School of MedicineResearch 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.