Browsing by Author "Taylor, Robert E."

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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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    Evaluation of aldehyde dehydrogenase 1 promoter polymorphisms identified in human populations
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2003-09) Spence, John P.; Liang, Tiebing; Eriksson, C. J. Peter; Taylor, Robert E.; Wall, Tamara L.; Ehlers, Cindy L.; Carr, Lucinda G.; Department of Medicine, IU School of Medicine
    BACKGROUND: Cytosolic aldehyde dehydrogenase, or ALDH1A1, functions in ethanol detoxification, metabolism of neurotransmitters, and synthesis of retinoic acid. Because the promoter region of a gene can influence gene expression, the ALDH1A1 promoter regions were studied to identify polymorphism, to assess their functional significance, and to determine whether they were associated with a risk for developing alcoholism. METHODS: Sequence analysis was performed in the promoter region by using Asian, Caucasian, and African American subjects. The resulting polymorphisms were assessed for frequency in Asian, Caucasian, Jewish, and African American populations and tested for associations with alcohol dependence in Asian and African American populations of alcoholics and controls. The functional significance of each polymorphism was determined through in vitro expression analysis by using HeLa and HepG2 cells. RESULTS: Two polymorphisms, a 17 base pair (bp) deletion (-416/-432) and a 3 bp insertion (-524), were discovered in the ALDH1A1 promoter region: ALDH1A1*2 and ALDH1A1*3, respectively. ALDH1A1*2 was observed at frequencies of 0.035, 0.023, 0.023, and 0.012 in the Asian, Caucasian, Jewish, and African American populations, respectively. ALDH1A1*3 was observed only in the African American population, at a frequency of 0.029. By using HeLa and HepG2 cells for in vitro expression, the activity of the luciferase reporter gene was significantly decreased after transient transfection of ALDH1A1*3-luciferase compared with the wild-type construct ALDH1A1*1-luciferase. In an African American population, a trend for higher frequencies of the ALDH1A1*2 and ALDH1A1*3 alleles was observed in a population of alcoholics (p = 0.03 and f = 0.12, respectively) compared with the control population. CONCLUSIONS: ALDH1A1*2 and ALDH1A1*3 may influence ALDH1A1 gene expression. Both ALDH1A1*2 and ALDH1A1*3 produce a trend in an African American population that may be indicative of an association with alcoholism; however, more samples are required to validate this observation. The underlying mechanisms contributing to these trends are still unknown.
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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.