Genome-wide association study meta-analysis of the Alcohol Use Disorder Identification Test (AUDIT) in two population-based cohorts (N=141,932)

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.; Clarke, Toni‐Kim

doi:10.1101/275917

Cited by 21 publications

(30 citation statements)

References 45 publications

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“…Broad sense heritability estimates of 25-61% for alcohol consumption have previously been reported from studies of twins 1, 2, 5 . The SNP effects for alcohol consumption were estimated at 6%, which again are lower than, but closer to, estimates reported in the UK Biobank for alcohol consumption (13%) and AUDIT scores in the 23andMe sample (12%) 28,36 . Previous studies have suggested that genetic interactions and improper modeling of the environment can inflate heritability estimates 37,38 .…”

Section: Discussionsupporting

confidence: 45%

Genetic and shared couple environmental contributions to smoking and alcohol use in the UK population

Clarke

Adams

Howard

et al. 2019

Preprint

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Alcohol use and smoking are leading causes of death and disability worldwide. Both genetic and environmental factors have been shown to influence individual differences in the use of these substances. In the present study we tested whether genetic factors, modelled alongside common family environment, explained phenotypic variance in alcohol use and smoking behaviour in the Generation Scotland (GS) family sample of up to 19,377 individuals. SNP and pedigree-associated effects combined explained between 18% and 41% of the variance in substance use. Shared couple effects explained a significant amount of variance across all substance use traits, particularly alcohol intake, for which 38% of the phenotypic variance was explained. We tested whether the within-couple substance use correlations were due to assortative mating by testing the association between partner polygenic risk scores in 34,987 couple pairs from the UK Biobank (UKB). Only couples' smoking status PRSs were significantly associated (b=0.01, S.E=0.005, p=0.02). However, an individual's alcohol PRS was associated with their partner's phenotype (b=0.04, S.E=0.007, p < 2 x 10 -7 ). In support of this, G carriers of a functional ADH1B polymorphism (rs1229984), known to be associated with greater alcohol intake, were found to consume less alcohol if they had a partner who carried an A allele at this SNP. Together these results show that the shared couple environment contributes significantly to patterns of substance use. It is unclear whether this is due to shared environmental factors, assortative mating, or indirect genetic effects. Future studies would benefit from longitudinal data and larger sample sizes to assess this further.

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Section: Discussionsupporting

confidence: 45%

Genetic and shared couple environmental contributions to smoking and alcohol use in the UK population

Clarke

Adams

Howard

et al. 2019

Preprint

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“…Summary-level data of large GWAS were obtained for ADHD (clinically diagnosed versus controls, n=55,374 4 ), smoking (initiation (ever regularly smoked or ≥100 cigarettes during lifetime), n=1,232,091; cigarettes per day, n=337,334; cessation (former versus current smokers), n=547,219 17 ; lifetime smoking, n=463,003 35 ), alcohol use (drinks per week, n=941,280 17 ; alcohol problems (AUDIT total score: Alcohol Use Disorders Identification Test), n=121,604 19 ; alcohol dependence (clinically diagnosed versus controls), n=46,568 36 ), cannabis use (initiation (ever used during lifetime), n=162,082 16 ) and coffee consumption (cups per day, n=91,462 18 ). When smoking initiation, cigarettes per day, smoking cessation or alcohol drinks per week was the outcome in the MR analysis, data of one of the included cohorts, 23andMe, were not available, resulting in sample sizes of n=632,783, n=263,954, n=312,821 and n= 537,341, respectively.…”

Section: Datamentioning

confidence: 99%

“…Family studies have shown that ADHD and substance use are moderately to highly heritable, and indicate shared genetic risk factors 14,15 . Overlap in genetic risk has also been examined in recent genome-wide association studies (GWAS) of ADHD and substance use 4,[16][17][18][19] . Substantial genetic correlations were found for ADHD with ever versus never smoking (rg=0.…”

Section: Introductionmentioning

confidence: 99%

Investigating causal pathways between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization

Treur

Demontis

Sallis

et al. 2019

Preprint

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BackgroundAttention-deficit hyperactivity disorder (ADHD) has consistently been associated with substance (ab)use, but the nature of this association is not fully understood. In view of preventive efforts, a vital question is whether there are causal effects, from ADHD to substance use and/or from substance use to ADHD.MethodsWe applied bidirectional Mendelian randomization using summary-level data from the largest available genome-wide association studies (GWASs) on ADHD, smoking (initiation, cigarettes/day, cessation, and a compound measure of lifetime smoking), alcohol use (drinks/week and alcohol use disorder), cannabis use (initiation and cannabis use disorder (CUD)) and coffee consumption (cups/day). Genetic variants robustly associated with the ‘exposure’ were selected as instruments and then identified in the ‘outcome’ GWAS. Effect estimates from individual genetic variants were combined with inverse-variance weighted regression and five sensitivity analyses were applied (weighted median, weighted mode, MR-Egger, generalized summary-data-based MR, and Steiger filtering).ResultsWe found strong evidence that liability to ADHD increases likelihood of smoking initiation and also cigarettes per day among smokers, decreases likelihood of smoking cessation, and increases likelihood of cannabis initiation and CUD. In the other direction, there was evidence that liability to smoking initiation and CUD increase ADHD risk. There was no clear evidence of causal effects between liability to ADHD and alcohol or caffeine consumption.ConclusionsWe find evidence for causal effects of liability to ADHD on smoking and cannabis use, and of liability to smoking and cannabis use on ADHD risk, indicating bidirectional pathways. Further work is needed to explore causal mechanisms.

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“…the relative proportion of one's diet derived from fat, carbohydrate and protein), it was reported that FGF21, a predominantly liver-derived hormone, suppresses intake of simple sugars and alcohol in mice and consumption of the artificial sweetener saccharin in primates (Talukdar et al 2016;von Holstein-Rathlou et al 2016). Since then, these findings have been replicated and generalized in mice and humans (Evangelou et al 2018;Frayling et al 2018;Meddens et al 2018;Sanchez-Roige et al 2018).…”

Section: Introductionmentioning

confidence: 96%

Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

Holstein-Rathlou

Gillum

2019

The Journal of Physiology

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Fibroblast growth factor 21 (FGF21) is a liver‐derived hormone with pleiotropic metabolic effects. Its production is induced by various dietary imbalances in mice (including low‐protein and ketogenic diets, fructose feeding and ethanol), hinting that it might influence food preference given the role of the liver in maintaining homeostatic levels of circulating nutrients. In 2016, it was shown that FGF21 selectively inhibits consumption of sugars and the primary product of their fermentation, ethanol, but not intake of fat, protein or complex carbohydrates. Since then, studies have sought to unravel this selectivity, its physiological purpose and translational relevance, as well as delineate the neural mechanisms involved. Initially found to impact ingestive behaviours in mice and non‐human primates, FGF21 is also induced in humans by sugars and, far more dramatically, by acute alcohol intake. Genetic studies have revealed that patterns of weekly candy and alcohol consumption are associated with genetic variants in FGF21 and its co‐receptor β‐klotho (KLB), suggesting that liking for sugar, and fermented sugar, may be influenced by natural variation in FGF21 signal strength in humans. Herein, we discuss our nascent understanding of FGF21 as a selective negative regulator of sugar and alcohol appetite as well as reasons why such a peculiar system may have evolved in mammals. Uncovering the regulatory network governing sugar, and fermented sugar, intake could provide new opportunities to improve dietary choices in a population suffering from Western diet‐induced diseases fuelled in part by a runaway sweet – and alcohol – tooth.

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Genome-wide association study meta-analysis of the Alcohol Use Disorder Identification Test (AUDIT) in two population-based cohorts (N=141,932)

Cited by 21 publications

References 45 publications

Genetic and shared couple environmental contributions to smoking and alcohol use in the UK population

Genetic and shared couple environmental contributions to smoking and alcohol use in the UK population

Investigating causal pathways between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization

Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

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