A Scientist Development Award (K21) is requested to allow the Candidate- to develop an independent program of research to examine in women compared with men (i) genetic influences on smoking; (ii) the relationship between genetic influences on smoking behavior, and genetic factors responsible for use of and dependence on other substances (using alcohol as a model system); (iii) possible mediators of genetic influence on use of and the development of dependence on nicotine and other substances, i.e., personality (e.g., Neuroticism and Novelty-Seeking), lifetime depression and anxiety disorders, and adolescent conduct disorder; and (iv) vulnerability and protective factors (e.g. spouse's smoking or successful cessation) which contribute to the initiation of cigarette smoking, transitions in amount used, smoking persistence and dependence. Despite the importance of smoking from a public health perspective, there has been little research designed specifically to understand the genetic contributions to risk of becoming a long-term (""""""""persistent"""""""") smoker. Yet re-analyses of existing data have given heritability estimates for smoking persistence as high as 53-71% in women as well as men. A program of secondary data-analysis is proposed that will provide more information about the inheritance of smoking behavior, identify the most important aspects of smoking to select for genetic study, and permit necessary skills acquisition in quantitative genetic methodology. Findings will be compared from large sample questionnaire twin surveys in Finland, Sweden, Australia (""""""""1981"""""""" and """"""""1989"""""""" cohort twins), and the U.S. (Virginia mailed questionnaire twin survey). Further analyses will be conducted using data from telephone-interview assessments from some 6,000 twins from the Australian twin panel, and data from a longitudinal study of female adolescent pairs (in progress) that include assessments of alcohol dependence, illicit drug use, and other Axis I disorders. To implement this program of research, funds are requested to allow specialized training and additional mentoring in the following areas: (i) quantitative genetics; (ii) psychometric evaluation (to optimize phenotype definition for smoking research); and (iii) statistical epidemiology; as well as for (iv) exposure to genetic research on nicotine sensitivity in rodents. In the long-term, self- report interview and questionnaire data on twin pairs are limited in how far they can advance our understanding of genetic influences on smoking behavior and funds are also requested for training and/or coursework in (i) molecular genetics; and (ii) the administration of nicotine, and physiologic and biochemical measures of nicotine response; as well as for (iii) the ascertainment of a sample for use as pilot data in the preparation of grants for the future conduct of a) nicotine challenge research, and b) genetic association studies.
