HENRI BEGLEITER MEMORIAL SYMPOSIUM
Co-Chairs:
Nora D. Volkow, M.D.
Director
National Institute on Drug Abuse
T.K. Li, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
Overview
Endophenotypes are proximal to gene function, and hence provide
a powerful approach to uncovering genes and genetic risk factors
that contribute to complex behavioral phenotypes, such as alcohol
dependence and drug abuse. This symposium addresses how
some genetically influenced differences in susceptibility are unique
to alcoholism (e.g., metabolic differences), whereas others (such as
impulsivity) influence a range of related outcomes, including
externalizing, mood disorders, and substance abuse.
Genetic Epidemiological Perspectives on Alcohol Use and Dependence
Kenneth S. Kendler, M.D.
Both twin and adoption studies have consistently shown that the levels of alcohol consumption and liability to alcohol abuse and dependence (AAD) are substantially influenced by genetic factors. I will address three issues being examined in the genetic epidemiology of alcohol use and AAD.
The first issue is that of specificity. Are genes that influence risk to AAD largely specific to this condition, or are they shared with other substance use disorders and/or externalizing disorders? Two studies that address this question are reviewed; both were performed in male and female twin pairs from the Virginia Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD). AAD shares substantial genetic risk factors with other externalizing disorders, as well as with the abuse or dependence of nicotine, cannabis, and cocaine. However, both studies also found substantial sources of genetic effects on AAD that are not shared with other syndromes. Thus, genetic risk factors for AAD are partly nonspecific and partly specific.
The second issue to be explored is the developmental influences of genetic and shared environment factors on alcohol intake. A sample of male–male twin pairs from VATSPSUD shows rather striking developmental effects. Twin resemblance for the quantity of alcohol consumed in early adolescence is entirely environmental in origin. Genetic factors become progressively more important as individuals move into late adolescence and then early adulthood.
The third issue concerns genetic control of exposure to the environment. Genes likely contribute to the etiologic pathway to AAD, in part through impacting on exposure to deviant environments, including drug availability. A developmental twin study of peer deviance in the VATSPSUD shows increasing genetic effects on this key aspect of social environment as individuals move from childhood to adolescence to young adulthood. The same study also shows that genetic influences on self-reported alcohol availability become stronger when individuals leave home and begin young adulthood. Finally, genetic epidemiological methods are applied to parsing causal pathways between deviance in the individual (as operationalized by the criteria for conduct disorder) and deviance in the peer group.
These results, which can hopefully be applied directly to the study of AAD, show genetic causal paths from individual to peer deviance, and shared environmental causal pathways in the reverse direction, from peer deviance to individual deviance. Genetic epidemiologic methods are now moving beyond simple models of heritability to explore critical questions about the dynamic contribution of genetic and environmental risk factors to individual differences in alcohol consumption and the risk for AAD.
Neurophysiological Endophenotypes, Central Nervous System Disinhibition, and Risk for Alcohol Dependence and Related Disorders
Bernice Porjesz, Ph.D.
Biological endophenotypes are more proximal to gene function than psychiatric diagnosis, and provide a powerful strategy when searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, and thus, provide a more direct connection with underlying biological vulnerability.
The Collaborative Study on the Genetics of Alcoholism has used heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We found significant linkage and association between brain oscillations and genes involved with inhibitory neural networks (e.g., GABRA2 [gamma-aminobutyric acid A receptor, alpha2], CHRM2 [cholinergic receptor, muscarinic 2]), including frontal networks that are deficient in individuals with alcohol dependence, impulsivity, and related disinhibitory disorders. We reported significant linkage and linkage disequilibrium for the beta frequency of the electroencephalograph and GABRA2 (a GABAA receptor gene on chromosome 4), which we found is also associated with diagnosis of alcohol dependence and related disorders. We also reported significant linkage and linkage disequilibrium between the theta and delta event-related oscillations underlying P3 generation to target stimuli and CHRM2, a cholinergic muscarinic receptor gene on chromosome 7, that we found is also associated with diagnosis of alcohol dependence and related disorders. Thus, the identification of genes important for the expression of the endophenotypes (brain oscillations) helps to identify genes that increase the susceptibility for risk of alcohol dependence and related disorders. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of complex disorders. We present our recent genetic findings related to brain oscillations and central nervous system disinhibition.
Functional Alleles and Intermediate Phenotypes in Alcoholism and Dyscontrol Disorders
David Goldman, M.D.
Dr. Henri Begleiter’s 1984 paper in Science, “Event-Related Brain Potentials in Boys at Risk for Alcoholism,” opened a paradigm shift in genetic studies of addiction. Working with a team of investigators that included Dr. Bernice Porjesz, Dr. Begleiter discovered that alcohol-naïve, at-risk boys already had a neurobiological indicator of attentional deficits, which directly pointed to the action of genes or early life experience. Addiction studies with intermediate phenotypes and endophenotypes (heritable and disease-associated intermediate phenotypes) now encompass stress/anxiety responses, behavioral control, reward, and obsessionality, as well as pharmacokinetic and pharmacodynamic responses to the drugs themselves. An important aspect of the intermediate phenotype approach was the ability to predict effects of functional alleles critical to the neurobiology being accessed. For frontal cognition, which Dr. Begleiter had primarily studied with electrophysiological techniques, a functional catecholamine methyl transferase (COMT) Val158Met polymorphism was replicably linked to working memory and task switching, with the Met158 allele that leads to higher dopamine levels coherently associated to better performance and greater cortical efficiency as assessed by cognitive functional magnetic resonance imaging. In recent years, we reported a series of linkages of functional alleles to another major neurobiology of addictions: variation in resiliency and vulnerability to stress/anxiety responses. Such variation is a key to drug-induced disruptions of the homeostatic maintenance of mood, and addicted patients who have suffered such disruptions remain vulnerable to stress-induced relapse.
For example, a chromosome 4 signal to alcoholism (reported by the Collaborative Study on the Genetics of Alcoholism [COGA] and us) and beta electroencephalograph (reported by COGA) were isolated to the GABAA alpha 2 subunit gene region by Dr. Howard Edenberg and collaborators at COGA. Isolation of the chromosome 4 linkage signal region sets the stage for locus identification and for a gene for alcoholism, and associated electrophysiological variation represents one culmination of a multicenter collaborative study that Dr. Begleiter originated and co-led with his late colleague Dr. Ted Reich. We and others replicated the GABAA finding at the haplotype and allele level, and we found that the linkage is anxiety-mediated. For the serotonin transporter (HTT) and COMT, common functional alleles lead to increased stress and emotional responses, and do so by actions on amygdala function as well as alterations to the modulatory effects of other brain regions, including the frontal cortex.
At the behavioral level, COMT and HTT modulate variation in anxiety, obsessionality, suicidality, and cognitive performance. Pursuing the intermediate phenotype trail blazed by Dr. Begleiter, we recently discovered a functional haplotype of neuropeptide Y (NPY), an anxiolytic neuropeptide that counteracts corticotropin-releasing hormone activations that are important in addicted individuals. The NPY haplotype predicts lower in vivo mRNA and NPY levels and is functional in cells transfected in vitro. The primary sequence alteration was identified in the promoter region. The NPY haplotype predicts trait anxiety, measured as harm avoidance. Coherently, the low-expression haplotype predicts enhanced amygdala fMRI metabolic response to emotional challenge, and poorer ability to respond to a pain/stress challenge by releasing endogenous opioids and displacing the exogenous ligand, [11C]carfentanil.
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