OBJECTIVE:
Alcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with a proxy measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits.


METHOD:
This study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank [N=121,604] and 23andMe [N=20,328]) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1-3, which focus on consumption (AUDIT-C), and for scores on items 4-10, which focus on the problematic consequences of drinking (AUDIT-P).


RESULTS:
The GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (rg=0.76-0.92) and DSM-IV alcohol dependence (rg=0.33-0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (rg=0.22), major depressive disorder (rg=0.26), and attention deficit hyperactivity disorder (rg=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (rg=-0.24) and ADHD (rg=-0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (rg=0.82) while retaining most subjects.


CONCLUSIONS:
AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.

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

Impulse control is becoming a critical survival skill for the twenty-first century. Impulsivity is implicated in virtually all externalizing behaviours and disorders, and figures prominently in the aetiology and long-term sequelae of substance use disorders (SUDs). Despite its robust clinical and predictive validity, the study of impulsivity is complicated by its multidimensional nature, characterized by a variety of trait-like personality dimensions, as well as by more state-dependent neurocognitive dimensions, with variable convergence across measures. This review provides a hierarchical framework for linking self-report and neurocognitive measures to latent constructs of impulsivity and, in turn, to different psychopathology vulnerabilities, including substance-specific addictions and comorbidities. Impulsivity dimensions are presented as novel behavioural targets for prevention and intervention. Novel treatment approaches addressing domains of impulsivity are reviewed and recommendations for future directions in research and clinical interventions for SUDs are offered. This article is part of the theme issue 'Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.

https://royalsocietypublishing.org/doi/pdf/10.1098/rstb.2018.0137

Impulsivities and addictions: a multidimensional integrative framework informing assessment and interventions for substance use disorders.

Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment (bred High Responders (bHR) vs. Low Responders (bLR)). To identify genes underlying the response to selection, we phenotyped and genotyped 558 rats from an F2 cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait. Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which the Pik3c3 gene is located. There were no significant loci for PavCA. We identified a missense variant in the Plekhf1 gene on the chromosome 1:95 Mb QTL and Fancf and Gas2 as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing the Pkhd1l1 and Trhr genes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats. The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders.

/pdf/genome-wide-association-study-in-a-rat-model-of-temperament-2gcm7ctk.pdf

Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits

The current study examines a recently developed short version of the UPPS-P Impulsive Behavior Scale. Participants were 251 undergraduate students (59.3% male; mean age = 21.16 (SD = 4.18); 72% Caucasian). The short version generally replicated the internal consistency (0.74 – 0.88 across subscales) and inter-scale correlations of the full UPPS-P. Moreover, the estimated loss of shared variance was small (0% – 6.4% reductions across subscales) as compared to a 66% timesavings. Structural equation modeling replicated previously supported factor structures and relationships to external outcomes using the full UPPS-P. The short UPPS-P scale should be considered a valid and reliable alternative to the full UPPS-P.

Examination of a Short Version of the UPPS-P Impulsive Behavior Scale

Background: Impulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse Methods: In collaboration with the genetics company 23andMe, Inc, we performed several genome-wide association studies (GWAS) on measures of impulsive personality traits (the short version of the UPPSP Impulsive Behavior Scale, and the Barratt Impulsiveness Scale [BIS-11]) and drug experimentation (the number of drug classes an individual has tried in their lifetime) in up to 22,861 male and female adult research participants of European ancestry Results: Impulsive personality traits and drug experimentation showed SNP-heritabilities that ranged from 5 to 11% Genetic variants in the CADM2 locus were significantly associated with the UPPSP Sensation Seeking subscale (P = 83 x 10-9, rs139528938) and showed a suggestive association with drug experimentation (P = 30 x 10-7, rs2163971; r2 = 068 with rs139528938); CADM2 has been previously associated with measures of risky behaviors and self-reported risk tolerance, cannabis initiation, alcohol consumption, as well as information speed processing, body mass index (BMI) variation and obesity Furthermore, genetic variants in the CACNA1I locus were significantly associated with the UPPSP Negative Urgency subscale (P = 38 x 10-8, rs199694726) Multiple subscales from both UPPSP and BIS showed strong genetic correlations (>05) with drug experimentation and other substance use traits measured in independent cohorts, including smoking initiation, and lifetime cannabis use Several UPPSP and BIS subscales were genetically correlated with attention-deficit/hyperactivity disorder (rg = 030-051, p < 869 x 10-3), supporting their validity as endophenotypes Conclusions: Our findings demonstrate a role for common genetic contributions to individual differences in impulsivity Furthermore, our study is the first to provide a genetic dissection of the relationship between different types of impulsive personality traits and various psychiatric disorders

/pdf/genome-wide-association-studies-of-impulsive-personality-3qw5y8074x.pdf

Genome-wide association studies of impulsive personality traits (BIS-11 and UPPSP) and drug experimentation in up to 22,861 adult research participants

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Genome-wide association studies of impulsive personality traits (BIS-11 and UPPSP) and drug experimentation in up to 22,861 adult research participants