H epatic encephalopathy (HE) continues to be a major clinical problem. In subjects with acute liver failure, patients can succumb to a neurologic death, with brain edema and intracranial hypertension. 1 In patients with cirrhosis, the Child classification recognizes the prognostic significance of HE. 2 The current decade has not witnessed major therapeutic breakthroughs in this area. However, there is a need to delineate better research tools in preparation for new developments, and define mild forms of the disorder and their response to treatment. Drugs that work directly on the brain will become increasingly available for clinical testing. The current epidemic of hepatitis C is increasing the number of patients with cirrhosis and raising questions about alterations in biological functions, such as sleep and appetite, that are intertwined with the significance and pathogenesis of minimal (subclinical) encephalopathy.Under this light, the Organisation Mondiale de Gastroentér-ologie commissioned a Working Party to reach a consensus in this area and to present it at the 11th World Congress of Gastroenterology (WCOG) in Vienna (1998). The study of the changes in mental state in patients with liver disease requires the expertise of several disciplines, including hepatology, neurology, and neuropsychology, all represented in the composition of the Working Party. Four questions were tackled:1 Gastroenterology; EEG, electroencephalogram; NCT, number connection test; TIPS, transjugular portal-systemic shunt; PET, positron emission tomography. From the

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM-IV diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case/control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E-13) and African ancestries (rs2066702; p = 2.2E-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, ADHD, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non-pathological drinking behaviors.

Cross-sectional and longitudinal analyses indicated that neurobehavioral disinhibition is a component of the liability to early age at onset of substance use disorder.

Background Two competing concepts address the development of involvement with psychoactive substances: the “gateway hypothesis” (GH) and common liability to addiction (CLA). Method The literature on theoretical foundations and empirical findings related to both concepts is reviewed. Results The data suggest that drug use initiation sequencing, the core GH element, is variable and opportunistic rather than uniform and developmentally deterministic. The association between risks for use of different substances, if any, can be more readily explained by common underpinnings than by specific staging. In contrast, the CLA concept is grounded in genetic theory and supported by data identifying common sources of variation in the risk for specific addictions. This commonality has identifiable neurobiological substrate and plausible evolutionary explanations. Conclusions Whereas the “gateway” hypothesis does not specify mechanistic connections between “stages”, and does not extend to the risks for addictions, the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co-occurrence, and establishes a theoretical and empirical foundation to research in etiology, quantitative risk and severity measurement, as well as targeted non-drug-specific prevention and early intervention.

Summary Background Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings We identified two genome-wide significant loci: a novel chromosome 7 locus ( FOXP2 , lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10 −9 ) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2 , lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10 −9 ). Cannabis use disorder and cannabis use were genetically correlated ( r g 0·50, p=1·50 × 10 −21 ), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Serv...

The etiology of early age onset substance use disorder (SUD), an Axis I psychiatric illness, is examined from the perspective of the multifactorial model of complex disorders. Beginning at conception, genetic and environment interactions produce a sequence of biobehavioral phenotypes during development which bias the ontogenetic pathway toward SUD. One pathway to SUD is theorized to emanate from a deviation in somatic and neurological maturation, which, in the context of adverse environments, predisposes to affective and behavioral dysregulation as the cardinal SUD liability-contributing phenotype. Dysregulation progresses via epigenesis from difficult temperament in infancy to conduct problems in childhood to substance use by early adolescence and to severe SUD by young adulthood.

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Research findings suggest that alcoholism and drug abuse may be predisposed by inherited behavioral propensities or temperaments. These inherited predispositions, through interaction with the physical and social environments, shape the development of personality. As discussed herein, there is strong evidence linking certain personality characteristics, specifically antisocial and neurotic traits, with the risk for substance abuse. Thus, personality and its precursor, temperament, comprise an important diathesis. However, an adverse outcome also depends on a variety of developmental and environmental factors.The risk for developing a substance-abuse problem is not equally distributed in the general population. Numerous factors present in childhood augment the risk for the subsequent development of either an alcohol or a drug problem. Some of the most salient psychosocial risk factors include urban demographic status, low socioeconomic status, weak cultural-religious affiliation, easy access to drugs and alcohol, family history of alcohol or drug use, family discord, identification with a nonnormative peer group, alienation, and weak inculcation of nor-