Papers by Victor Hesselbrock
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2010
Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of ... more Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype-frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1 M microarray were selected from the theta ERO GWAS for replication in family-based samples (N ¼ 1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P ¼ 3.68 Â 10 À6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P ¼ 1.53 Â 10 À4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case-controls (P ¼ 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case-control and family-based samples (P ¼ 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders.
Archives of general …, Jan 1, 2004
Further Analyses of Genetic Association Between GRM8 and Alcohol Dependence Symptoms Among Young Adults
Journal of studies on alcohol and drugs, 2015
The gene GRM8, a metabotropic glutamate receptor, has emerged as a gene of interest for its possi... more The gene GRM8, a metabotropic glutamate receptor, has emerged as a gene of interest for its possible role in the development of alcohol dependence, with evidence of association with an electrophysiological endophenotype and level of response to alcohol as well as suggestive evidence of association with alcohol dependence. The present study further investigated the association between GRM8 and alcohol dependence symptom counts among young adults using a new sample of individuals collected as part of the prospective sample (ages 18-26 years; N = 842) from the Collaborative Study on the Genetics of Alcoholism (COGA). Two single-nucleotide polymorphisms were significantly associated with alcohol dependence in European Americans using the Nyholt corrected p value of .007: rs886003 (β = -.212, p = .0002) and rs17862325 (β = -.234, p < .0001), but not in African Americans, likely because of the lower power to detect association in this group. These results further implicate the role of ...
Are genetic variants for tobacco smoking associated with cannabis involvement?
Drug and alcohol dependence, Jan 4, 2015
Cannabis users are highly likely to also be tobacco cigarette smokers and a proportion of this co... more Cannabis users are highly likely to also be tobacco cigarette smokers and a proportion of this comorbidity is attributable to shared genetic influences. Three large meta-analyses of genomewide association studies (GWAS) of tobacco smoking have identified multiple genomewide significant (p<5×10(-8)) single nucleotide polymorphisms (SNPs). We examine whether these SNPs are associated with tobacco smoking and with cannabis involvement in an independent sample. Eleven SNPs associated with cigarettes per day (CPD), ever versus never smoking and current smoking/smoking cessation at p<5×10(-8) were selected from three published meta-analyses. Association analyses were conducted with similar tobacco smoking measures in 2716 European-American subjects from the Study of Addictions Genes and Environment (SAGE) and with lifetime and current cannabis use and DSM-IV cannabis abuse/dependence. Cannabis use and tobacco smoking correlated at 0.54. Rs16969968 in CHRNA5 (and its proxy, rs1051730...
Electroencephalography and clinical neurophysiology, 1998
The P3 event-related brain potential (ERP) is a positive-going voltage change of scalp-recorded e... more The P3 event-related brain potential (ERP) is a positive-going voltage change of scalp-recorded electroencephalographic activity that occurs between 300-500 ms after stimulus onset. It is elicited when a stimulus is perceived, memory operations are engaged, and attentional resources are allocated toward its processing. Because this ERP component reflects fundamental cognitive processing, it has found wide utility as an assessment of human mental function in basic and clinical studies. In particular, P3 attributes are heritable and have demonstrated considerable promise as a means to identify individuals at genetic risk for alcoholism. We have conducted a quantitative linkage analysis on a large sample from families with a high density of affected individuals. The analyses suggest that several regions of the human genome contain genetic loci related to the generation of the P3 component of the ERP, which are possible candidate loci underlying the functional organization of human neur...
Background: Suicide and suicidal behavior are prevalent among individuals with psychiatric disord... more Background: Suicide and suicidal behavior are prevalent among individuals with psychiatric disorders, including alcohol dependence. A genome screen was performed in multiplex alcohol dependent families ascertained as part of the Collaborative Study on the Genetics of Alcoholism to identify chromosomal regions of interest related to two types of suicidal behavior: suicide attempts and suicidality.
Background: Endophenotypes reflect more proximal effects of genes than diagnostic categories, hen... more Background: Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis.
Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism, 2002
Alcoholism is a disease that runs in families and results at least in part from genetic risk fact... more Alcoholism is a disease that runs in families and results at least in part from genetic risk factors. The Collaborative Study on the Genetics of Alcoholism (COGA) is a Federally funded effort to identify and characterize those genetic factors. The study involves more than 1,000 alcoholic subjects and their families, with researchers conducting comprehensive psychological, physiological, electrophysiological, and genetic analyses of the participants. These analyses have identified several traits, or phenotypes, that appear to be genetically determined, such as the presence of alcohol dependence, the level of response to alcohol, the presence of coexisting depression, or the maximum number of drinks a person consumes per occasion. Genetic analyses have identified regions on several chromosomes that are associated with these phenotypes and need to be studied further.
Journal of Clinical Child & Adolescent Psychology, 2014
We tested hypotheses that greater connectedness to parent(s) is associated with lower risk for no... more We tested hypotheses that greater connectedness to parent(s) is associated with lower risk for nonlethal suicidal thoughts and behavior (STB), termed direct protective effects, and that parent connectedness serves to moderate (lower) the risk for STB associated with psychopathology including major depressive episode (MDE), termed moderating protective effects. Independent samples of children and adolescents recruited for a multicenter study of familial alcoholism were studied. Generalized estimating equation models were used that adjusted for age, sex, and youth psychopathology variables. The sample for Study 1 was assessed at baseline and about 2-and 4-year follow-ups, with baseline characteristics of n ¼ 921, M age ¼ 14.3 AE 1.8 years, and 51.8% female. The sample for Study 2 was assessed at baseline and about 5-year follow-up, with baseline characteristics of n ¼ 867, M age ¼ 12.0 AE 3.2 years, and 51.0% female. In both studies, increased perceived connectedness to father but not mother was associated with lower risk for measures of STB, consistent with direct protective effects. In Study 1, measures of parent connectedness were associated with lower risk for STB but only for youth that did not experience MDE (or alcohol use disorder), inconsistent with moderating protective effects. Study 2 showed that connectedness to fathers was associated with lower risk for suicide plans or attempts (severe STB) but not frequent thoughts of death or dying (nonsevere STB). Improved connectedness to fathers may lower risk for STB in children and adolescents, consistent with direct protective effects. Hypotheses about moderating protective effects were not supported.
Polygenic Risk for Externalizing Disorders: Gene-by-Development and Gene-by-Environment Effects in Adolescents and Young Adults
Clinical Psychological Science, 2014
In this project, we aimed to bring large-scale gene identification findings into a developmental ... more In this project, we aimed to bring large-scale gene identification findings into a developmental psychopathology framework. Using a family-based sample, we tested whether polygenic scores for externalizing disorders-based on single nucleotide polymorphism weights derived from genome-wide association study results in adults (n = 1,249)-predicted externalizing disorders, subclinical externalizing behavior, and impulsivity-related traits adolescents (n = 248) and young adults (n = 207), and whether parenting and peer factors in adolescence moderated polygenic risk to predict externalizing disorders. Polygenic scores predicted externalizing disorders in adolescents and young adults, even after controlling for parental externalizing disorder history. Polygenic scores also predicted subclinical externalizing behavior and impulsivity traits in the adolescents and young adults. Adolescent parental monitoring and peer substance use moderated polygenic scores to predict externalizing disorders. This illustrates how state of the science genetics can be integrated with psychological science to identify how genetic risk contributes to the development of psychopathology.
Are there subgroups of bulimia nervosa based on comorbid psychiatric disorders?
The International journal of eating disorders, 2005
The current study sought to determine whether there are subtypes of bulimia nervosa (BN) differen... more The current study sought to determine whether there are subtypes of bulimia nervosa (BN) differentiated by comorbid psychiatric disorders. Data on comorbid psychiatric diagnoses in female relatives of probands and controls in the Collaborative Study of the Genetics of Alcoholism (COGA) who met criteria for BN (as outlined in the 3rd Rev. ed. of the Diagnostic and Statistical Manual of Mental Disorders) were analyzed using latent class analysis. Resulting latent classes were compared on a variety of variables related to impulsive behaviors and psychological functioning. The best-fitting solution, a two-class model, yielded one class (72%) characterized by substance dependence, depression, antisocial personality disorder (ASPD), and anxiety disorders, and another characterized by depression. The highly comorbid class had more suicidality, more daily smokers, sought help for emotional problems, and had lower Global Assessment of Functioning (GAF) scores compared with those in the comor...
Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families
Drug and alcohol dependence, 2014
The age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for a... more The age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA). Genomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs. This family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10(-9)) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were al...
Predictors of subgroups based on maximum drinks per occasion over six years for 833 adolescents and young adults in COGA
Journal of studies on alcohol and drugs, 2014
A person's pattern of heavier drinking often changes over time, especially during the early d... more A person's pattern of heavier drinking often changes over time, especially during the early drinking years, and reflects complex relationships among a wide range of characteristics. Optimal understanding of the predictors of drinking during times of change might come from studies of trajectories of alcohol intake rather than cross-sectional evaluations. The patterns of maximum drinks per occasion were evaluated every 2 years between the average ages of 18 and 24 years for 833 subjects from the Collaborative Study on the Genetics of Alcoholism. Latent class growth analysis identified latent classes for the trajectories of maximum drinks, and then logistic regression analyses highlighted variables that best predicted class membership. Four latent classes were found, including Class 1 (69%), with about 5 maximum drinks per occasion across time; Class 2 (15%), with about 9 drinks at baseline that increased to 18 across time; Class 3 (10%), who began with a maximum of 18 drinks per o...
Motives for alcohol-and/or tobacco addicted patients to seek medical help
60% of tobacco dependents describe themselves as “dissonant” smokers. They try temporarily or per... more 60% of tobacco dependents describe themselves as “dissonant” smokers. They try temporarily or permanently to reduce their smoking or even try to quit. Knowing that smoking leads to sequelae, knowing their withdrawal symptoms, this group often needs an impulse from the social environment (partner, work place etc.) or somatic symptoms (shortness of breath, stomach pain, pregnancy etc.) to quit. By contacting a therapist, the dissonant smoker group shows that they have realized their nicotine problem. When these individuals get effective help, they are easy to motivate to reduce or even quit smoking.
Alcoholism-clinical and Experimental Research - ALCOHOL CLIN EXP RES, 2002
Background: Subtle electroencephalographic (EEG) abnormalities have been detected among subjects ... more Background: Subtle electroencephalographic (EEG) abnormalities have been detected among subjects with depressed affect. The present study attempted to discern whether these abnormalities reflect a main effect or an interaction between depression and either of two family history variables-a family history of alcoholism or a family history of depression.
Adolescent health brief Paternal Alcoholism and Youth Substance Abuse: The Indirect Effects of Negative Affect, Conduct Problems, and Risk Taking
This longitudinal study followed 200 adolescents into early adulthood to explore the potential me... more This longitudinal study followed 200 adolescents into early adulthood to explore the potential mediating roles that hostility, sadness, conduct problems, and risk-taking play in the relationship between paternal alcoholism and substance abuse. Results indicated that paternal alcoholism predicted hostility; in turn, hostility predicted risk taking, which predicted substance abuse. © 2008 Society for Adolescent Medicine. All rights reserved. Negative affect may play an important mediating role in the relationship between parental alcoholism and offspring (COA) substance abuse. To date, most studies that have examined the relationship between negative affect and COA substance abuse have examined a general indicator of negative affect. However, recent research suggests that certain components of negative affect may be more strongly related to substance abuse than others (1). Therefore, one goal of this study was to compara- tively examine the potential mediating roles that hostility and...
The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the biological treatment of paraphilias
World Journal of Biological Psychiatry, 2010
“Never Believe an Alcoholic”? On the Validity of Self-Report Measures of Alcohol Dependence and Related Constructs
Substance Use & Misuse, 1983
A study of 114 male and female alcoholics was conducted to evaluate the validity of information o... more A study of 114 male and female alcoholics was conducted to evaluate the validity of information obtained by means of self-report questionnaires. Factor analysis was used to derive composite measures of alcohol dependence, withdrawal symptomatology, pathological intoxication, and alcoholic psychosis. Validation was conducted by comparing these measures with independent and external criteria; that is drinking estimates made by collateral informants, measures of general alcohol involvement, and drinking behavior 6 months after treatment. The results support each type of validity, and thereby contradict the assumption that the alcoholics&#39; self-reports were not accurate. The question of unreliable self-report data due to the demand characteristics of the situation under which the information is obtained is also addressed.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1992
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Papers by Victor Hesselbrock