Genome-Wide Association Study Meta-Analysis of the Alcohol Use Disorders Identification Test (AUDIT) in Two Population-Based Cohorts

Sanchez‐Roige, Sandra; Palmer, Abraham A.; Fontanillas, Pierre; Elson, Sarah L.; Adams, Mark; Howard, David M.; Edenberg, Howard J.; Davies, Gail; Crist, Richard C.; Deary, Ian J.; McIntosh, Andrew M.; Clarke, Toni‐Kim

doi:10.1176/appi.ajp.2018.18040369

Cited by 385 publications

(454 citation statements)

References 46 publications

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“…Use and dependence are behaviors with different relationships to other genetically influenced traits, as has been shown for alcohol use vs. alcohol dependence 39,40 . The The BEND4 locus was also significantly confirmed by gene-based association analysis (p=9.9×10 -6 ).…”

Section: Discussionmentioning

confidence: 97%

Leveraging genome-wide data to investigate differences between opioid usevs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium

Polimanti

Walters

Johnson³

et al. 2019

Preprint

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To provide novel insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing up to 4,503 OD cases, 4,173 opioid-exposed controls, and 32,500 opioid-unexposed controls. Among the variants identified, rs9291211 was associated with OE (a comparison of exposed vs. unexposed controls; z=-5.39, p=7.2×10 -8 ). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N>360,000) found association of this variant with propensity to use dietary supplements (p=1.68×10 -8 ). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (z=4.69, p=10 -6 ), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (z=5.55, p=2.9×10 -8 ) and a significant association with musculoskeletal disorders in the UK Biobank (p=4.88×10 -7 ). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (N=466,571) was positively associated with OD (OD cases vs. unexposed controls, p=8.1×10 -5 ; OD cases vs. exposed controls, p=0.054) and OE (exposed controls vs. unexposed controls, p=3.6×10 -5 ). A PRS based on a GWAS of neuroticism (N=390,278) was positively associated with OD (OD cases vs. unexposed controls, p=3.2×10 -5 ; OD cases vs. exposed controls, p=0.002) but not with OE (p=0.671). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls (exposed vs. unexposed) in studies of addiction.

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Section: Discussionmentioning

confidence: 97%

Leveraging genome-wide data to investigate differences between opioid usevs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium

Polimanti

Walters

Johnson³

et al. 2019

Preprint

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“…6 However, candidate gene research has generated inconsistent results, likely a reflection of being underpowered to robustly detect moderations, false positives, and publication bias. 13,14 Furthermore, the use of single genes in G×E studies does not align with our current molecular genetic understanding that complex behaviors, including alcohol use, 15 problems, 16 and dependence, 17 have a polygenic architecture, driven by many genetic variants of very small effect. 18,19 Large sample sizes are needed to detect robust genetic associations for complex behavioral outcomes in genome-wide association studies (GWAS), which use data from the entire genome rather than relying on predefined SNPs.…”

Section: Meaningmentioning

confidence: 99%

“…We note that alcohol consumption and problematic use, though highly correlated, have distinct genetic influences. 47 We ran a series of sensitivity analyses to determine if recent GWAS focused on alcohol problems or dependence 16,17 provided better assessments of genetic liability for alcohol misuse (see supplemental information). However, in each case, the scores derived from GSCAN were the most predictive.…”

Section: Genome-wide Polygenic Scoresmentioning

confidence: 99%

Polygenic Risk for Alcohol Misuse is Moderated by Romantic Partnerships: Primarily in Men

Barr¹,

Kuo²,

Alıev

et al. 2019

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Importance: Problematic alcohol use remains a leading influence on preventable mortality and morbidity across the globe. Those in committed relationships consistently report lower levels of alcohol misuse and problems. Objective:To determine 1) whether genetic risk for alcohol misuse is moderated by romantic relationships (gene-environment interaction; GxE), and 2) whether GxE results are consistent across sex.Design: Data came from the young adult wave of the Finnish Twin Study (FinnTwin12), a nationally representative sample of twins. Predictors included genome-wide polygenic scores (GPS), derived from a recent genome-wide association study (GWAS) of alcohol consumption in ~1 million participants; and participant reports of relationship status. Setting: FinlandParticipants: An intensively studied subset of FinnTwin12 received a diagnostic interview during the young adult phase (1,312 of 1,347 individuals provided genotypic data). The analytic sample includes those with complete interview and genetic data (N=1,201, 54% female). Exposure: Self-reported involvement in a romantic partnership. Main Outcomes and Measures:Drinking frequency, intoxication frequency, and DSM-IV alcohol dependence (AD) symptoms from a diagnostic interview.Results: GPS predicted drinking frequency (b = 0.109; 95% CI = 0.051, 0.167), intoxication frequency (b = 0.111; 95% CI = 0.054, 0.168), and AD symptoms (b = 0.123; 95% CI = 0.064, 0.182). Relationship moderated the association between GPS and drinking frequency (b = -0.105; 95% CI = -0.211, -0.001), intoxication frequency (b = -0.118; 95% CI = -0.220, -0.015), and AD symptoms (b = -0.119; 95% CI = -0.229, -0.010). The interaction for drinking frequency was not significant after correcting for covariates. There was a 3-way interaction between sex, relationship status, and GPS for intoxication frequency (b = 0.223; 95% CI = 0.014, 0.432), with the two-way interaction of relationship status and PRS on intoxication frequency being significant only in men. Conclusions and Relevance:Being in a relationship reduced the association between genetic predisposition and high risk drinking. Part of the protective effect of committed partnerships on alcohol misuse observed in epidemiological research may be in limiting genetic liability. However, this protective effect was largely limited to males, mapping onto earlier findings suggesting that males benefit more from romantic partnerships.

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“…SNPs associated with AUDIT scores were obtained from a GWAS in 121,604 individuals of European ancestry from the UK Biobank Cohort [28]. The sample was 56.2% female and the mean age was 56.1 (SD 7.7)…”

Section: Alcohol Use Disorder Identification Test (Audit)mentioning

confidence: 99%

Association between alcohol consumption and Alzheimer’s disease: A Mendelian randomization Study

Andrews

Anstey

2017

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Observational studies have suggested that a U-shaped relationship exists between alcohol consumption and Alzheimer's disease, with light-moderate drinkers at lower risk of developing Alzheimer's disease. A two-sample Mendelian randomization approach was used to examine whether alcohol consumption causally effects the risk of developing Alzheimer's disease. We used summary level genome-wide association data for alcohol consumption from the UK biobank, alcohol dependence from the Netherlands Twin Register (NTR) and the Netherlands Study of Depression and Anxiety, and Alzheimer's disease from the International Genomics of Alzheimer's Project. Variants associated with alcohol consumption were combined using an inverse variance weighted fixed-effects approach. We found no evidence of a causal association between genetically predicted alcohol consumption These findings contrast with those of recent systematic reviews of observational studies.

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Genome-Wide Association Study Meta-Analysis of the Alcohol Use Disorders Identification Test (AUDIT) in Two Population-Based Cohorts

Cited by 385 publications

References 46 publications

Leveraging genome-wide data to investigate differences between opioid usevs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium

Leveraging genome-wide data to investigate differences between opioid usevs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium

Polygenic Risk for Alcohol Misuse is Moderated by Romantic Partnerships: Primarily in Men

Association between alcohol consumption and Alzheimer’s disease: A Mendelian randomization Study

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