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Background: Early identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM‐5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD. Methods: We studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM‐5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM‐IV alcohol dependence or DSM‐5 AUD and 1616 were alcohol‐exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first‐degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH−). PRS were derived from a meta‐analysis of a genome‐wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity. Results: AUD cases had higher PRS than controls with PRS increasing as the number of DSM‐5 diagnostic criteria increased (p‐values ≤ 1.85E−05) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p‐value = 7.57E−08) and 1.86 (95% CI: 1.35 to 2.56, p‐value = 1.32E−04) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first‐degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM‐5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p‐values ≤6.7E−11). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p‐values ≤6.8E−10). Conclusions: Both PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits. [ABSTRACT FROM AUTHOR]

Background: Rodent paradigms and human genome‐wide association studies (GWAS) on drug use have the potential to provide biological insight into the pathophysiology of addiction. Methods: Using GeneWeaver, we created rodent alcohol and nicotine gene‐sets derived from 19 gene expression studies on alcohol and nicotine outcomes. We partitioned the SNP heritability of these gene‐sets using four large human GWAS: (1) alcoholic drinks per week, (2) problematic alcohol use, (3) cigarettes per day, and (4) smoking cessation. We benchmarked our findings with curated human alcohol and nicotine addiction gene‐sets and performed specificity analyses using other rodent gene‐sets (e.g., locomotor behavior) and other human GWAS (e.g., height). Results: The rodent alcohol gene‐set was enriched for heritability of drinks per week, cigarettes per day, and smoking cessation, but not problematic alcohol use. However, the rodent nicotine gene‐set was not significantly associated with any of these traits. Both rodent gene‐sets showed enrichment for several non‐substance‐use GWAS, and the extent of this relationship tended to increase as a function of trait heritability. In general, larger gene‐sets demonstrated more significant enrichment. Finally, when evaluating human traits with similar heritabilities, both rodent gene‐sets showed greater enrichment for substance use traits. Conclusion: Our results suggest that rodent gene expression studies can help to identify genes that contribute to the heritability of some substance use traits in humans, yet there was less specificity than expected. We outline various limitations, interpretations, and considerations for future research. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies (GWAS) of alcohol dependence (AD) and related phenotypes have identified multiple loci, but the functional variants underlying the loci have in most cases not been identified. Noncoding variants can influence phenotype by affecting gene expression; for example, variants in the 3′ untranslated regions (3′UTR) can affect gene expression posttranscriptionally. Methods: We adapted a high‐throughput assay known as PASSPORT‐seq (parallel assessment of polymorphisms in miRNA target sites by sequencing) to identify among variants associated with AD and related phenotypes those that cause differential expression in neuronal cell lines. Based upon meta‐analyses of alcohol‐related traits in African American and European Americans in the Collaborative Study on the Genetics of Alcoholism, we tested 296 single nucleotide polymorphisms (SNPs with meta‐analysis p values ≤ 0.001) that were located in 3′UTRs. Results: We identified 60 SNPs that affected gene expression (false discovery rate [FDR] < 0.05) in SH‐SY5Y cells and 92 that affected expression in SK‐N‐BE(2) cells. Among these, 30 SNPs altered RNA levels in the same direction in both cell lines. Many of these SNPs reside in the binding sites of miRNAs and RNA‐binding proteins and are expression quantitative trait loci of genes including KIF6,FRMD4A,CADM2,ADD2,PLK2, and GAS7. Conclusion: The SNPs identified in the PASSPORT‐seq assay are functional variants that might affect the risk for AD and related phenotypes. Our study provides insights into gene regulation in AD and demonstrates the value of PASSPORT‐seq as a tool to screen genetic variants in GWAS loci for one potential mechanism of action. [ABSTRACT FROM AUTHOR]

Background: Genomewide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples. Methods: In 6,731 European Americans who had been exposed to alcohol, we examined whether polygenic risk scores (PRS) from a GWAS of weekly alcohol consumption in the UK Biobank predicted variance in 6 alcohol‐related phenotypes: alcohol use, maximum drinks within 24 hours (MAXD), total score on the Self‐Rating of the Effects of Ethanol Questionnaire (SRE‐T), DSM‐IV alcohol dependence (DSM4AD), DSM‐5 alcohol use disorder symptom counts (DSM5AUDSX), and reduction/cessation of problematic drinking. We also examined the extent to which an single nucleotide polymorphism (rs1229984) in ADH1B, which is strongly associated with both alcohol consumption and dependence, contributed to the polygenic association with these phenotypes and whether PRS interacted with sex, age, or family history of alcoholism to predict alcohol‐related outcomes. We performed mixed‐effect regression analyses, with family membership and recruitment site included as random effects, as well as survival modeling of age of onset of DSM4AD. Results: PRS for alcohol consumption significantly predicted variance in 5 of the 6 outcomes: alcohol use (Δmarginal R2 = 1.39%, Δ area under the curve [AUC] = 0.011), DSM4AD (Δmarginal R2 = 0.56%; ΔAUC = 0.003), DSM5AUDSX (Δmarginal R2 = 0.49%), MAXD (Δmarginal R2 = 0.31%), and SRE‐T (Δmarginal R2 = 0.22%). PRS were also associated with onset of DSM4AD (hazard ratio = 1.11, p = 2.08e−5). The inclusion of rs1229984 attenuated the effects of the alcohol consumption PRS, particularly for DSM4AD and DSM5AUDSX, but the PRS continued to exert an independent effect for all 5 alcohol measures (Δmarginal R2 after controlling for ADH1B = 0.14 to 1.22%). Interactions between PRS and sex, age, or family history were nonsignificant. Conclusions: Genetic propensity for typical alcohol consumption was associated with alcohol use and was also associated with 4 of the additional 5 outcomes, though the variance explained in this sample was modest. Future GWAS that focus on the multifaceted nature of AUD, which goes beyond consumption, might reveal additional information regarding the polygenic underpinnings of problem drinking. [ABSTRACT FROM AUTHOR]

Background: Previous studies indicate that low initial sensitivity to alcohol may be a risk factor for later alcohol misuse. Evidence suggests that initial sensitivity is influenced by genetic factors, but few molecular genetic studies have been reported. Methods: We conducted a meta‐analysis of 2 population‐based genome‐wide association studies of the Self‐Rating of the Effects of Alcohol scale. Our final sample consisted of 7,339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated single nucleotide polymorphism (SNP)‐based heritability and conducted a series of secondary aggregate genetic analyses. Results: No individual locus reached genome‐wide significance. Gene and set based analyses, both overall and using tissue‐specific expression data, yielded largely null results, and genes previously implicated in alcohol problems and consumption were overall not associated with initial sensitivity. Only 1 gene set, related to hormone signaling and including core clock genes, survived correction for multiple testing. A meta‐analysis of SNP‐based heritability resulted in a modest estimate of hSNP2 = 0.19 (SE = 0.10), though this was driven by 1 sample (N = 3,683, hSNP2 = 0.36, SE = 0.14, p = 0.04). No significant genetic correlations with other relevant outcomes were observed. Conclusions: Findings yielded only modest support for a genetic component underlying initial alcohol sensitivity. Results suggest that its biological underpinnings may diverge somewhat from that of other alcohol outcomes and may be related to core clock genes or other aspects of hormone signaling. Larger samples, ideally of prospectively assessed samples, are likely necessary to improve gene identification efforts and confirm the current findings. Initial sensitivity to alcohol is associated with later problematic alcohol‐related outcomes. The current study found evidence of aggregate genetic influences on initial sensitivity, though no individual SNP met genome‐wide significance criteria. Further analyses suggest that the biology of initial sensitivity may diverge from that of other alcohol outcomes. As with other complex traits, how initial sensitivity is assessed is likely critical to the identification of robust genetic signals. [ABSTRACT FROM AUTHOR]