GENETIC ARCHITECTURE OF RISK FOR ANTISOCIAL ALCOHOLISM

This is an application for a Mentored Research Scientist Development Award (K01). This award is requested to provide an opportunity for the candidate to complete a transition from basic behavior-genetic research to a clinically based program of research focused on understanding the influence of heredity on risk for antisocial alcoholism (AAL) and its comorbid disorders (CDs). The training setting is the University of Michigan Department of Psychiatry and Mental Health Research Institute. It is clear that alcoholism is not a Mendelian trait, the factors associated with its intergenerational transmission are multiple and interacting. This proposal is designed to provide the candidate with experience on several fronts, all of which will be necessary to better understand the complexities of the etiology and developmental trajectories of AAL and its CDs within a developmental systems framework. These fronts include (a) multivariate statistics, (b) molecular genetics, (c) longitudinal/developmental study designs and (d) complex adaptive systems. Implementation of these skills in the conduct of small scale research projects will position the candidate for submission of an R01 application during the award period. This application describes studies that would take place during the MRSDA period that would enable the candidate to enhance his scientific skills along each of these fronts. The major study proposed would serve to collect and archive genetic samples from 291 families participating in the University of Michigan/Michigan State University Longitudinal Study directed by Dr. Robert A. Zucker, that are well characterized phenotypically. Candidate gene analyses will be conducted to assess potential associations between genes in the serotonergic system and behavioral undercontrol in children, a risk factor for developing AAL. This sample represents an important resource to study risk for AAL and its CDs. Archiving the genetic samples will position the candidate to take advantage of expected technological advances in rapid and large-scale scoring of single nucleotide polymorphisms (SNPs) and in complexity-oriented analytic techniques. Other projects proposed include secondary analysis of a family-based genetic study data set, the development of molecular genetic markers and additional candidate gene analyses. This award would enhance the candidate's potential for developing an independent research program to study the genetics of antisocial alcoholism and its comorbid disorders.