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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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    Incorporating Functional Genomic Information to Enhance Polygenic Signal and Identify Variants Involved in Gene-by-Environment Interaction for Young Adult Alcohol Problems
    (Wiley, 2018) Salvatore, Jessica E.; Savage, Jeanne E.; Barr, Peter; Wolen, Aaron R.; Aliev, Fazil; Vuoksimaa, Eero; Latvala, Antti
    BackgroundCharacterizing aggregate genetic risk for alcohol misuse and identifying variants involved in gene-by-environment (GxE) interaction effects has so far been a major challenge. We hypothesized that functional genomic information could be used to enhance detection of polygenic signal underlying alcohol misuse and to prioritize identification of single nucleotide polymorphisms (SNPs) most likely to exhibit GxE effects. MethodsWe examined these questions in the young adult FinnTwin12 sample (n=1,170). We used genomewide association estimates from an independent sample to derive 2 types of polygenic scores for alcohol problems in FinnTwin12. Genomewide polygenic scores included all SNPs surpassing a designated p-value threshold. DNase polygenic scores were a subset of the genomewide polygenic scores including only variants in DNase I hypersensitive sites (DHSs), which are open chromatin marks likely to index regions with a regulatory function. We conducted parallel analyses using height as a nonpsychiatric model phenotype to evaluate the consistency of effects. For the GxE analyses, we examined whether SNPs in DHSs were overrepresented among SNPs demonstrating significant GxE effects in an interaction between romantic relationship status and intoxication frequency. ResultsContrary to our expectations, we found that DNase polygenic scores were not more strongly predictive of alcohol problems than conventional polygenic scores. However, variants in DNase polygenic scores had per-SNP effects that were up to 1.4 times larger than variants in conventional polygenic scores. This same pattern of effects was also observed in supplementary analyses with height. In GxE models, SNPs in DHSs were modestly overrepresented among SNPs with significant interaction effects for intoxication frequency. ConclusionsThese findings highlight the potential utility of integrating functional genomic annotation information to increase the signal-to-noise ratio in polygenic scores and identify genetic variants that may be most susceptible to environmental modification.
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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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    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.