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Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity.

ABSTRACT: 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.

SUBMITTER: Edwards AC

PROVIDER: S-EPMC6286211 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity.

Edwards Alexis C AC Deak Joseph D JD Gizer Ian R IR Lai Dongbing D Chatzinakos Chris C Wilhelmsen Kirk P KP Lindsay Jonathan J Heron Jon J Hickman Matthew M Webb Bradley T BT Bacanu Silviu-Alin SA Foroud Tatiana M TM Kendler Kenneth S KS Dick Danielle M DM Schuckit Marc A MA

Alcoholism, clinical and experimental research 20181028 12

<h4>Background</h4>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.<h4>Methods</h4>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% femal ...[more]

PMID: 30276832

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Project description:IntroductionCraving is being considered for inclusion in the Diagnostic and Statistical Manual (DSM) DSM-5. However, little is known of its genetic underpinnings - specifically, whether genetic influences on craving are distinct from those influencing DSM-IV alcohol dependence.MethodAnalyses were conducted in a sample of unrelated adults ascertained for alcohol dependence (N=3976). Factor analysis was performed to examine how alcohol craving loaded with the existing DSM-IV alcohol dependence criteria. For genetic analyses, we first examined whether genes in the dopamine pathway, including dopamine receptor genes (DRD1, DRD2, DRD3, DRD4) and the dopamine transporter gene (SLC6A3), which have been implicated in neurobiological studies of craving, as well as alpha-synuclein (SNCA), which has been previously found to be associated with craving, were associated with alcohol craving in this sample. Second, in an effort to identify novel genetic variants associated with craving, we conducted a genomewide association study (GWAS). For variants that were implicated in the primary analysis of craving, we conducted additional comparisons - to determine if these variants were uniquely associated with alcohol craving as compared with alcohol dependence. We contrasted our results to those obtained for DSM-IV alcohol dependence, and also compared alcohol dependent individuals without craving to non-dependent individuals who also did not crave alcohol.ResultsTwenty-one percent of the full sample reported craving alcohol. Of those reporting craving, 97.3% met criteria for DSM-IV alcohol dependence with 48% endorsing all 7 dependence criteria. Factor analysis found a high factor loading (0.89) for alcohol craving. When examining genes in the dopamine pathway, single nucleotide polymorphisms (SNPs) in DRD3 and SNCA were associated with craving (p<0.05). There was evidence for association of these SNPs with DSM-IV alcohol dependence (p<0.05) but less evidence for dependence without craving (p>0.05), suggesting that the association was due in part to craving. In the GWAS, the greatest evidence of association with craving was for a SNP in the integrin alpha D (ITGAD) gene on chromosome 7 (rs2454908; p=1.8×10(-6)). The corresponding p-value for this SNP with DSM-IV alcohol dependence was similar (p=4.0×10(-5)) but was far less with dependence without craving (p=0.02), again suggesting the association was due to alcohol craving. Adjusting for dependence severity (number of endorsed criteria) attenuated p-values but did not eliminate association.ConclusionsCraving is frequently reported by those who report multiple other alcohol dependence symptoms. We found that genes providing evidence of association with craving were also associated with alcohol dependence; however, these same SNPs were not associated with alcohol dependence in the absence of alcohol craving. These results suggest that there may be unique genetic factors affecting craving among those with alcohol dependence.

Project description:BackgroundMedical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progression has not yet been determined.MethodsUsing data from Swedish national registries for a cohort born from 1932 to 1970 (N = 1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data.ResultsWe identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A = 0.32) and men (A = 0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance.ConclusionsA moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.

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Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity.

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Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity.

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