Browsing by Author "Scott, Denise M."

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    ERRATUM: Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans
    (Wiley, 2019-11) Wetherill, Leah; Lai, Dongbing; Johnson, Emma C.; Anokhin, Andrey; Bauer, Lance; Bucholz, Kathleen K.; Dick, Danielle M.; Hariri, Ahmad R.; Hesselbrock, Victor; Kamarajan, Chella; Kramer, John; Kuperman, Samuel; Meyers, Jacquelyn L.; Nurnberger, John I., Jr.; Schuckit, Marc; Scott, Denise M.; Taylor, Robert E.; Tischfield, Jay; Porjesz, Bernice; Goate, Alison M.; Edenberg, Howard J.; Foroud, Tatiana; Bogdan, Ryan; Agrawal, Arpana; Medical and Molecular Genetics, School of Medicine
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    Genome-wide admixture mapping of DSM-IV alcohol dependence, criterion count, and the self-rating of the effects of ethanol in African American populations
    (Wiley, 2021-04) Lai, Dongbing; Kapoor, Manav; Wetherill, Leah; Schwandt, Melanie; Ramchandani, Vijay A.; Goldman, David; Chao, Michael; Almasy, Laura; Bucholz, Kathleen; Hart, Ronald P.; Kamarajan, Chella; Meyers, Jacquelyn L.; Nurnberger, John I., Jr.; Tischfield, Jay; Edenberg, Howard J.; Schuckit, Marc; Goate, Alison; Scott, Denise M.; Porjesz, Bernice; Agrawal, Arpana; Foroud, Tatiana; Medical and Molecular Genetics, School of Medicine
    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.
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    Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria
    (Wiley, 2019-06-04) Lai, Dongbing; Wetherill, Leah; Bertelsen, Sarah; Carey, Caitlin E.; Kamarajan, Chella; Kapoor, Manav; Meyers, Jacquelyn L.; Anokhin, Andrey P.; Bennett, David A.; Bucholz, Kathleen K.; Chang, Katharine K.; Jager, Philip L. De; Dick, Danielle M.; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John I.; Raj, Towfique; Schuckit, Marc; Scott, Denise M.; Taylor, Robert E.; Tischfield, Jay; Hariri, Ahmad R.; Edenberg, Howard J.; Agrawal, Arpana; Bogdan, Ryan; Porjesz, Bernice; Goate, Alison M.; Foroud, Tatiana; Medical and Molecular Genetics, School of Medicine
    Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (e.g., ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWASs of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7,418 (1,121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3,175 (585 families) African American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (p=4.16E-11) and Desire to cut drinking (p=1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, p=6.72E-09); rs1912461 (chromosome 15, Time spent drinking, p=1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, p=8.42E-11); rs7597960 (chromosome 2, Time spent drinking, p=1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (p<0.01; 0.61-1.82% of variance). Identified novel variants (i.e., rs1912461, rs61826952) were associated with differential central evoked theta power (loss minus gain; p=0.0037) and reward-related ventral striatum reactivity (p=0.008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.
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    Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans
    (Wiley, 2019-05-19) Wetherill, Leah; Lai, Dongbing; Johnson, Emma C.; Anokhin, Andrey; Bauer, Lance; Bucholz, Kathleen K.; Dick, Danielle M.; Hariri, Ahmad R.; Hesselbrock, Victor; Kamarajan, Chella; Kramer, John; Kuperman, Samuel; Meyers, Jacquelyn L.; Nurnberger, John I.; Schuckit, Marc; Scott, Denise M.; Taylor, Robert E.; Tischfield, Jay; Porjesz, Bernice; Goate, Alison M.; Edenberg, Howard J.; Foroud, Tatiana; Bogdan, Ryan; Agrawal, Arpana; Medical and Molecular Genetics, School of Medicine
    Genetic influences on alcohol and drug dependence partially overlap, however specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7,291 European-Americans (EA; 2,927 cases) and 3,132 African-Americans (AA: 1,315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h2 in EA=0.60, AA=0.37). The AA GWAS identified 3 regions with genome-wide significant (GWS; p<5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA+AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and 4 sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.
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    Interactions Between Alcohol Metabolism Genes and Religious Involvement in Association With Maximum Drinks and Alcohol Dependence Symptoms
    (Rutgers Center of Alcohol Studies, 2016-05) Chartier, Karen G.; Dick, Danielle M.; Almasy, Laura; Chan, Grace; Aliev, Fazil; Schuckit, Marc A.; Scott, Denise M.; Kramer, John; Bucholz, Kathleen K.; Bierut, Laura J.; Nurnberger, John Jr.; Porjesz, Bernice; Hesselbrock, Victor M.; Psychiatry, School of Medicine
    OBJECTIVE: Variations in the genes encoding alcohol dehydrogenase (ADH) enzymes are associated with both alcohol consumption and dependence in multiple populations. Additionally, some environmental factors have been recognized as modifiers of these relationships. This study examined the modifying effect of religious involvement on relationships between ADH gene variants and alcohol consumption-related phenotypes. METHOD: Subjects were African American, European American, and Hispanic American adults with lifetime exposure to alcohol (N = 7,716; 53% female) from the Collaborative Study on the Genetics of Alcoholism. Genetic markers included ADH1Brs1229984, ADH1B-rs2066702, ADH1C-rs698, ADH4-rs1042364, and ADH4-rs1800759. Phenotypes were maximum drinks consumed in a 24-hour period and total number of alcohol dependence symptoms according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Religious involvement was defined by self-reported religious services attendance. RESULTS: Both religious involvement and ADH1B-rs1229984 were negatively associated with the number of maximum drinks consumed and the number of lifetime alcohol dependence symptoms endorsed. The interactions of religious involvement with ADH1B-rs2066702, ADH1C-rs698, and ADH4-rs1042364 were significantly associated with maximum drinks and alcohol dependence symptoms. Risk variants had weaker associations with maximum drinks and alcohol dependence symptoms as a function of increasing religious involvement. CONCLUSIONS: This study provided initial evidence of a modifying effect for religious involvement on relationships between ADH variants and maximum drinks and alcohol dependence symptoms.