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    Genetic and environmental etiology of drinking motives in college students
    (Wiley, 2022) Savage, Jeanne E.; Peterson, Roseann E.; Aliev, Fazil; Dick, Danielle M.
    Background Drinking motives are robust proximal predictors of alcohol use behaviors and may mediate distinct etiological pathways in the development of alcohol misuse. However, little is known about the genetic and environmental etiology of drinking motives themselves and their potential utility as endophenotypes. Methods Here, we leverage a longitudinal study of college students from diverse racial/ethnic backgrounds (phenotypic N = 9889, genotypic N = 4855) to investigate the temporal stability and demographic and environmental predictors of four types of drinking motives (enhancement, social, coping, and conformity). Using genome-wide association study (GWAS) and in silico tools, we characterize their associated genes and genetic variants (single nucleotide polymorphisms or SNPs). Results Drinking motives were stable across four years of college (ICC >0.74). Some robust environmental predictors of alcohol misuse (parental autonomy granting and peer deviance) were broadly associated with multiple types of drinking motives, while others (e.g., trauma exposure) were type specific. Genome-wide analyses indicated modest SNP-based heritability (14-22%, n.s.) and several suggestive genomic loci that corroborate findings from previous molecular genetic studies (e.g., PECR and SIRT4 genes), indicating possible differences in the genetic etiology of positive versus negative reinforcement drinking motives that align with an internalizing/externalizing typology of alcohol misuse. Coping motives were significantly genetically correlated with alcohol use disorder diagnoses (r(g) = 0.71, p = 0.001). However, results from the genetic analyses were largely underpowered to detect significant associations. Conclusions Drinking motives show promise as endophenotypes but require further investigation in larger samples to further our understanding of the etiology of alcohol misuse.
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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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    Polygenic prediction of the phenome, across ancestry, in emerging adulthood
    (Cambridge Univ Press, 2018) Docherty, Anna R.; Moscati, Arden; Dick, Danielle; Savage, Jeanne E.; Salvatore, Jessica E.; Cooke, Megan; Aliev, Fazil
    BackgroundIdentifying genetic relationships between complex traits in emerging adulthood can provide useful etiological insights into risk for psychopathology. College-age individuals are under-represented in genomic analyses thus far, and the majority of work has focused on the clinical disorder or cognitive abilities rather than normal-range behavioral outcomes.MethodsThis study examined a sample of emerging adults 18-22 years of age (N = 5947) to construct an atlas of polygenic risk for 33 traits predicting relevant phenotypic outcomes. Twenty-eight hypotheses were tested based on the previous literature on samples of European ancestry, and the availability of rich assessment data allowed for polygenic predictions across 55 psychological and medical phenotypes.ResultsPolygenic risk for schizophrenia (SZ) in emerging adults predicted anxiety, depression, nicotine use, trauma, and family history of psychological disorders. Polygenic risk for neuroticism predicted anxiety, depression, phobia, panic, neuroticism, and was correlated with polygenic risk for cardiovascular disease.ConclusionsThese results demonstrate the extensive impact of genetic risk for SZ, neuroticism, and major depression on a range of health outcomes in early adulthood. Minimal cross-ancestry replication of these phenomic patterns of polygenic influence underscores the need for more genome-wide association studies of non-European populations.
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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.