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    Alcohol Metabolizing Polygenic Risk for Alcohol Consumption in European American College Students
    (Alcohol Res Documentation Inc Cent Alcohol Stud Rutgers Univ, 2018) Thomas, Nathaniel S.; Adkins, Amy; Aliev, Fazil; Edwards, Alexis C.; Webb, Bradley T.; Tiarsmith, E. Clare; Kendler, Kenneth S.
    Objective: Evidence suggests that the nature and magnitude of some genetic effects on alcohol use vary by age. We tested for moderation in the effect of an alcohol metabolizing polygenic score by time across the college years. Method: Participants (total n = 2,214) were drawn from three cohorts of undergraduate college students, who were assessed annually for up to 4 years starting in their freshman year. Polygenic risk scores (PRSs) were calculated from genes involved in the metabolism of alcohol, as many of these markers are among the best replicated in association studies examining alcohol use phenotypes. Linear mixed effects models were fit by maximum likelihood to test the main effects of time and the PRS on alcohol consumption, as well as moderation of the PRS effect on alcohol consumption by time. Results: In the main effects model, the fixed effects for time and the PRS were positively associated with alcohol consumption. The interaction term testing moderation of the PRS effect by time reached statistical significance and remained statistically significant after other relevant interaction effects were controlled for. The main effect of the PRS accounted for 0.2% of the variance in alcohol consumption, whereas the interaction of PRS effect and time accounted for 0.05%. Conclusions: Alcohol metabolizing genetic effects on alcohol use appear to be more influential in later years of college than in earlier years. Shifting environmental contexts, such as increased access to alcohol as individuals approach the legal age to purchase alcohol, may account for this association.
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    Genomic influences on alcohol problems in a population-based sample of young adults
    (Wiley, 2015) Edwards, Alexis C.; Aliev, Fazil; Wolen, Aaron R.; Salvatore, Jessica E.; Gardner, Charles O.; McMahon, George; Evans, David M.
    AimsAlcohol problems (AP) contribute substantially to the global disease burden. Twin and family studies suggest that AP are genetically influenced, although few studies have identified variants or genes that are robustly associated with risk. This study identifies genetic and genomic influences on AP during young adulthood, which is often when drinking habits are established. DesignWe conducted a genome-wide association study of AP. We further conducted gene-based tests, gene ontology analyses and functional genomic enrichment analyses to assess genomic factors beyond single variants that are relevant to AP. SettingThe Avon Longitudinal Study of Parents and Children, a large population-based study of a UK birth cohort. ParticipantsGenetic and phenotypical data were available for 4304 participants. MeasurementsThe AP phenotype was a factor score derived from items from the Alcohol Use Disorders Identification Test, symptoms of DSM-IV alcohol dependence, and three additional problem-related items. FindingsOne variant met genome-wide significance criteria. Four out of 22880 genes subjected to gene-based analyses survived a stringent significance threshold (q<0.05); none of these have been implicated previously in alcohol-related phenotypes. Several biologically plausible gene ontologies were statistically over-represented among implicated single nucleotide polymorphisms (SNPs). SNPs on the Illumina 550K SNP chip accounted for similar to 5% of the phenotypical variance in AP. ConclusionsGenetic and genomic factors appear to play a role in alcohol problems in young adults. Genes involved in nervous system-related processes, such as signal transduction and neurogenesis, potentially contribute to liability to alcohol problems, as do genes expressed in non-brain tissues.
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    Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students
    (Frontiers Media Sa, 2017) Webb, Bradley T.; Edwards, Alexis C.; Wolen, Aaron R.; Salvatore, Jessica E.; Aliev, Fazil; Riley, Brien P.; Sun, Cuie
    Background : Genetic factors impact alcohol use behaviors and these factors may become increasingly evident during emerging adulthood. Examination of the effects of individual variants as well as aggregate genetic variation can clarify mechanisms underlying risk. Methods : We conducted genome-wide association studies (GWAS) in an ethnically diverse sample of college students for three quantitative outcomes including typical monthly alcohol consumption, alcohol problems, and maximum number of drinks in 24 h. Heritability based on common genetic variants (h(SNP)(2)) was assessed. We also evaluated whether risk variants in aggregate were associated with alcohol use outcomes in an independent sample of young adults. Results : Two genome-wide significant markers were observed: rs11201929 in GRID1 for maximum drinks in 24 h, with supportive evidence across all ancestry groups; and rs73317305 in SAMD12 (alcohol problems), tested only in the African ancestry group. The h(SNP)(2) estimate was 0.19 (SE = 0.11) for consumption, and was non-significant for other outcomes. Genome-wide polygenic scores were significantly associated with alcohol outcomes in an independent sample. Conclusions : These results robustly identify genetic risk for alcohol use outcomes at the variant level and in aggregate. We confirm prior evidence that genetic variation in GRID1 impacts alcohol use, and identify novel loci of interest for multiple alcohol outcomes in emerging adults. These findings indicate that genetic variation influencing normative and problematic alcohol use is, to some extent, convergent across ancestry groups. Studying college populations represents a promising avenue by which to obtain large, diverse samples for gene identification.
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    Polygenic Risk Score Prediction of Alcohol Dependence Symptoms Across Population-Based and Clinically Ascertained Samples
    (Wiley, 2018) Savage, Jeanne E.; Salvatore, Jessica E.; Aliev, Fazil; Edwards, Alexis C.; Hickman, Matthew; Kendler, Kenneth S.; Macleod, John
    BackgroundDespite consistent evidence of the heritability of alcohol use disorders (AUDs), few specific genes with an etiological role have been identified. It is likely that AUDs are highly polygenic; however, the etiological pathways and genetic variants involved may differ between populations. The aim of this study was thus to evaluate whether aggregate genetic risk for AUDs differed between clinically ascertained and population-based epidemiological samples. MethodsFour independent samples were obtained: 2 from unselected birth cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC], N=4,304; FinnTwin12 [FT12], N=1,135) and 2 from families densely affected with AUDs, identified from treatment-seeking patients (Collaborative Study on the Genetics of Alcoholism, N=2,097; Irish Affected Sib Pair Study of Alcohol Dependence, N=706). AUD symptoms were assessed with clinical interviews, and participants of European ancestry were genotyped. Genomewide association was conducted separately in each sample, and the resulting association weights were used to create polygenic risk scores in each of the other samples (12 total discovery-validation pairs), and from meta-analyses within sample type. We then tested how well these aggregate genetic scores predicted AUD outcomes within and across sample types. ResultsPolygenic scores derived from 1 population-based sample (ALSPAC) significantly predicted AUD symptoms in another population-based sample (FT12), but not in either clinically ascertained sample. Trend-level associations (uncorrected p<0.05) were found for polygenic score predictions within sample types but no or negative predictions across sample types. Polygenic scores accounted for 0 to 1% of the variance in AUD symptoms. ConclusionsThough preliminary, these results provide suggestive evidence of differences in the genetic etiology of AUDs based on sample characteristics such as treatment-seeking status, which may index other important clinical or demographic factors that moderate genetic influences. Although the variance accounted for by genomewide polygenic scores remains low, future studies could improve gene identification efforts by amassing very large samples, or reducing genetic heterogeneity by informing analyses with other phenotypic information such as sample characteristics. Multiple complementary approaches may be needed to make progress in gene identification for this complex disorder.
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    The Rate of Change in Alcohol Misuse Across Adolescence is Heritable
    (Wiley, 2017) Edwards, Alexis C.; Heron, Jon; Vladimirov, Vladimir; Wolen, Aaron R.; Adkins, Daniel E.; Aliev, Fazil; Hickman, Matthew
    Background: Alcohol use typically begins during adolescence and escalates into young adulthood. This represents an important period for the establishment of alcohol use and misuse patterns, which can have psychosocial and medical consequences. Although changes in alcohol use during this time have been phenotypically characterized, their genetic nature is poorly understood. Methods: Participants of the Avon Longitudinal Study of Parents and Children completed the Alcohol Use Disorders Identification Test (AUDIT) 4 times from age 16 to 20. We used Mplus to construct a growth model characterizing changes in AUDIT scores across time (N = 4,545, where data were available for at least 2 time points). The slope of the model was used as the phenotype in a genomewide association study (N = 3,380), followed by secondary genetic analyses. Results: No individual marker met genomewide significance criteria. Top markers mapped to biologically plausible candidate genes. The slope term was moderately heritable (h(SNP)(2) = 0.26, p = 0.009), and replication attempts using a meta-analysis of independent samples provided support for implicated variants at the aggregate level. Nominally significant (p < 0.00001) markers mapped to putatively active genomic regions in brain tissue more frequently than expected by chance. Conclusions: These results build on prior studies by demonstrating that common genetic variation impacts alcohol misuse trajectories. Influential loci map to genes that merit additional research, as well as to intergenic regions with regulatory functions in the central nervous system. These findings underscore the complex biological nature of alcohol misuse across development.