Tamara L. Wall - US grants

It has been demonstrated that the prevalence of alcohol abuse and alcoholism varies widely among different ethnic groups. Asian populations appear to have lower rates of alcoholism than other ethnic groups, whereas certain tribes of Native Americans have very high rates of alcohol abuse. These differences in rates of alcoholism between various ethnic groups are thought to reflect a combination of sociocultural and biological factors. Several studies suggest that there may be racial and ethnic differences in biologic sensitivity to alcohol. The source of this disparity in alcohol sensitivity, while not well understood, presumably is the result of genetic differences in metabolic factors as well as differences in CNS "reactivity." This application proposes two studies which will evaluate reaction to alcohol in 21-25 year old Asian and Native American men. Subjects will be recruited and screened for personal and family history of alcoholism and other psychiatric disorders and will be genotyped for differences in alcohol metabolizing enzymes (ALDH2, ADH2, and ADH3 alleles). Subgroups of subjects will be identified based upon family history of alcoholism and genotyping variations. An alcohol/placebo challenge protocol will be used to evaluate behavioral, neuroendocrine, and electrophysiological reactivity to alcohol in matched subject subgroups. Subjects will also be followed over the course of the study to determine if they develop changes in alcohol drinking patterns or alcohol related problems. These studies have the potential to identify clinically relevant genetic markers of acute alcohol intoxication in addition to identifying possible cognitive, physiological, and/or neurochemical mechanisms which may be risk or protective factors for alcoholism or alcohol abuse.

Asians; liver metabolism; alcoholic beverage consumption; racial /ethnic difference; aldehyde dehydrogenases; alcohol dehydrogenase; pharmacogenetics; male; human subject; female;

The University of California, San Diego (UCSD), Department of Psychiatry hereby applies on behalf of Tamara L. Wall for an Independent Scientist Award (KO2) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The overall aim of the proposed Research Career Award is to free the candidate from clinical and administrative duties so that she may devote nearly full-time to continue and develop further her research evaluating risk and protective factors for alcohol involvement within different ethnic groups. Asian Americans and Native American Indians vary greatly with respect to patterns, prevalences, and consequences of alcohol use. These differences are hypothesized to result from a combination of biological and psychosocial factors. This application has two overall goals: 1) to complete two projects currently funded by NIAAA focused on understanding the effects of genetic influences on response to alcohol in Asian Americans and Native American Indians; and 2) to expand upon these studies by evaluating the combined contributions of biological and psychosocial influences on alcohol drinking patterns and problems within these ethnic groups using cross-sectional, and eventually longitudinal, data. Results obtained from these studies will provide important information regarding the complex relationship between biological and environmental aspects of vulnerability to, and protection from, alcoholism. The candidate has made a strong commitment to alcohol-related research. Activities for her continued career development will include: 1) intensive new training with leading research scientists in the importance of psychosocial factors in developmental models of alcohol use and alcohol problems, statistical modeling techniques, and longitudinal research design; 2) coursework on advanced structural modeling and the responsible conduct of research; and 3) participation in department seminars and scientific meetings.

DESCRIPTION: Asian Americans, as a whole, have lower rates of alcohol use and alcohol use disorders than other ethnic groups in the United States. Studies conducted in Asia, however, indicate that Koreans have a significantly higher lifetime prevalence of alcohol abuse and dependence than Chinese. There are also data to indicate that these two Asian American subgroups vary greatly with respect to patterns, prevalence and consequences of alcohol use. The overall objective of the proposed research project is to determine variables associated with alcohol involvement (alcohol consumption and alcohol-related problems) in 21-25 year old Chinese American and Korean American college students using a risk and protective factor approach. The risk and protective factor dimensions that will be evaluated will focus on factors related to alcohol use and alcohol-related problems in previous studies of Asians and other ethnic groups, including variation in three genes involved in alcohol metabolism (ALDH2, ADH2, and ADH3), other genetically influenced factors (e.g., family history of alcoholism), and psychosocial variables. It is hypothesized that Korean Americans will have fewer protective factors and more risk factors than Chinese Americans. In a subsample of participants, an alcohol and placebo challenge paradigm will be conducted to measure level of response to alcohol in Korean Americans with and without an alcoholic father. It is hypothesized that those with an alcoholic father will demonstrate less intense reactions to alcohol than matched controls without a family history of alcoholism. Additionally, this study proposes to explore, within the sample, potential mediating and moderating relationships between vulnerability factors and alcohol involvement. The study of two Asian American subgroups with significantly different patterns of alcohol consumption and alcoholism offers a unique opportunity to control the influence of some specific genetic factors (variation in the alcohol metabolism genes) while searching for additional influences on alcohol use behavior and how these factors may relate to promote or protect against alcohol problems. Ultimately, a better understanding of the factors associated with alcohol behavior in Asian Americans will contribute important information for understanding the causes of alcohol abuse and dependence and might aid in the development of efficacious and culturally sensitive prevention and intervention programs.

DESCRIPTION (provided by applicant): This application is a competitive renewal for an Independent Scientist Award. The candidate, Tamara L. Wall, Ph.D., Associate Professor of Psychiatry at the University of California, San Diego, proposes to continue her program of research focused on factors and processes that predispose and/or protect individuals, particularly ethnic minorities, from alcohol and other substance involvement. The research plan includes six projects, three of which have been funded and are ongoing; the other three are being considered for funding or are under scientific review. The candidate's career goals are: (1) to advance her progress in becoming a leader in the scientific study of biological and psychosocial influences that lead to differences in alcohol involvement; (2) to increase her expertise in statistical modeling techniques, genetics, and related methodological issues; and (3) to continue to mentor junior scientists. The candidate has made a strong commitment to alcohol-related research. Activities for her continued career development include: (1) consultation with leading research scientists; (2) coursework in the analysis of longitudinal and genetically informative data, and the responsible conduct of research; and (3) participation in department seminars and scientific meetings. Renewal of Dr. Wall's Independent Scientist Award will provide her the opportunity to continue to engage in research activities on nearly a full-time basis, thus ensuring her continued development as a scientist and as a mentor.

DESCRIPTION (provided by applicant): This application continues a multisite collaboration, initiated under DA 012845, to address critical issues in the genetic epidemiology of adolescent onset antisocial drug dependence. Addressing these issues requires sample sizes greater than a single site can reasonably attain, as well as the multidisciplinary expertise of psychiatrists, psychologists, and behavioral and molecular geneticists, that is difficult to provide at a single site. This collaboration includes longitudinal assessment of previously studied probands and siblings, and adds community controls. It will yield a total of ~800 clinical probands, together with their siblings, to assess differing developmental trajectories and clinical courses, and the role of comorbidity, early onset, and familial loading. After allowing for desistance, we anticipate a final sample of ~600 persistent cases, together with their siblings, and a matched sample of ~600 control subjects, for genetic association analyses of persistent, adolescent onset, antisocial substance dependence. The current application will use dense SNP association mapping to identify genetic loci predisposing to this pattern of behavior. The specific aims of the project are as follows: 1) We will complete the five year follow-up assessment of ~800 clinical probands, aged 19 though 23 years at follow-up, and their siblings, and ascertain a sample of matched control subjects from our existing databases together with 300 newly ascertained control subjects. The new assessments will be conducted at the San Diego and Denver sites. 2) We will assess differing developmental trajectories and clinical courses, and the role of comorbidity, early onset, and familial loading on these. The data set we are collecting would, even in the absence of a single DMA sample, represent a unique, and unsurpassed, research resource for studying the development and familial influences on adolescent antisocial drug dependence. 3) We will use Affymetrix SNP chip technology to genotype an average of 25 SNPs in each of 200 candidate genes for drug dependence vulnerability and/or conduct disorder. 4) We will conduct association analyses using the -600 persistent cases and their ~600 matched controls, and then conduct confirmatory tests of the best signals using a within-family association analysis (Laird and Lange, 2006). These analyses will confirm the significance and robustness of genetic associations with adolescent onset persistent antisocial drug dependence. 5) Through a continuation of our NIDA Genetics Consortium data sharing agreement, we will share all the core substance dependence and psychopathology phenotypic data, and DNA from lymphoblastoid cell lines established for the multisite samples. Our Affymetrix SNP chip will be made available, at cost, to any qualified researcher.

DESCRIPTION (provided by applicant): The research proposed in this application aims to understand genetic and environmental factors that promote desistance or continuation of problematic substance use and associated high-risk behaviors that began in adolescence. We propose an ~12-year follow-up (6 years after an initial 6-year follow-up) of an extremely affected adolescent sample as they transition into adulthood; this is a critical developmental period when we expect a portion of these individuals to decrease or desist problematic substance use and associated high-risk behaviors, while others will persist with the most serious, destructive behaviors leading to devastatingly high rates of morbidity and mortality. Our central goal is to understand the genetic and environmental factors that delineate these life trajectories. Results from our longitudinal research demonstrate that adolescent-onset substance users, who primarily exhibited abuse of and dependence on marijuana, nicotine, and alcohol during adolescence, progressed in the severity of their substance use five years later. As young adults, they report dramatically high rates of lifetime cocaine (29.2%), amphetamine (29.2%), and opiate (10.8%) use disorders as well as HIV/AIDS-related risk behaviors such as injection drug use (11%) and risky sexual behaviors. Indeed, when compared with community samples, these individuals report more than twice the number of lifetime sexual partners and a 33% higher rate of unprotected sex. Furthermore, they exhibit alarming rates of adult incarceration (55%) and early death (2.6%). This proposal extends our multiple-PI collaboration focused on the genetic epidemiology of adolescent-onset drug dependence. The three specific aims are to: 1) Identify distinct developmental trajectories of substance use, antisocial, and HIV risk behaviors in probands and siblings from adolescence to adulthood. a) Test initial characteristics of the adolescents, such as sex, severity of early onset substance use disorders (SUDs) and conduct disorder (CD), and neurocognitive functioning (e.g., disinhibition) that predict these trajectories and b) Test whether adult resources such as treatment for SUDs, housing stability, occupational stability, and social support are associated with these trajectories. 2) Determine the genetic and environmental architecture of developmental trajectories of substance use disorders, antisocial and HIV risk behaviors. a) Test the moderating role of social context, such as SES, criminal justice involvement, substance abuse treatment/self-help involvement, and stressful life events, in altering genetic influence and b) Test whether moderating effects vary across developmental periods (adolescence, young adulthood, and adulthood). 3) Test the influence of shared versus specific etiologic influences on measures of SUDs, antisocial behaviors, and HIV risk behaviors across development.