Richard J Rose, PhD - US grants

Twin, family and adoption data document genetic contributions to the development of alcoholism, but the specific pathways for these heritable effects remain unknown. Genetic influences on alcohol use and abuse appear to be modulated by age and gender and, perhaps by an individual's drinking history, and the nature of heritable influences on alcohol use may be quite distinguishable from the genetic pathways that predispose to alcohol abuse. Developmental genetic analyses that exploit twin-family designs can elucidate heritable mechanisms in the use and abuse of alcohol. Using the resources of the Indiana University Twin Panel, we propose two complementary studies: One will assess genetic influences on acute reactions to ethanol in young adult twins; the other will evaluate genetic, familial and gender sources of variation in alcohol use and abuse in extensive and innovative twin-family studies. Over a three-year period, 300 like-sex co-twins, ages 21-26, equally split by gender and zygosity but differing in familial risk for alcoholism and individual drinking history, will be studied in a laboratory assessment of psychophysiological, behavioral and subjective response to an ethonal load; these data will evaluate heritable variance in susceptibility to alcohol as a pathway for genetic influences in the development of alcoholism. Concurrently, questionnaire studies of self-reported use of alcohol and of personality dimensions predictive of alcohol abuse will be made in large samples of twins, their sibs and parents, in the extended kinships of monozygotic twin parents, and in balanced pedigrees formed by a singleton college student, a sibling and both parents. Retest reliability of dependent measures in the laboratory protocol and of self-reported use of alcohol will be established from repeat testing of a subset of subjects in both studies. Jointly, these three data-sets will yield significant information on the nature and magnitude of familial influences on frequency and quantity of alcohol use in 2500-3000 adolescent and adult members of 450-600 families. Parameter estimation of these data will permit robust and novel analyses of maternal effects, assortative mating, and gene by age by gender interactions in the familial aggregation of alcohol use and abuse.

This application requests support to initiate a research program directed to the familial nature of the use and abuse of alcohol, to assessment of age, gender, and social modulation of genetic influences on drinking during the critical developmental period from mid-adolescent to early adulthood, and to the early identification of familial and behavioral markers among those who are at risk for sustained abuse of alcohol. The research will use a unique resource: The Finnish Twin-Family Cohort, population-based, and linked to a nation-wide death, disease, and insurance registers. We propose a prospective study design in which five consecutive, nation-wide birth cohorts of adolescent twins, their siblings, parents, and selected siblings of both parents will be longitudinally studied. Over the course of a five-year period,> 12,500 members of 2,600 kinships of adolescent twins will be assessed with postal questionnaires. The study population will include > 1,600 pairs of like- sex twins, about 800 twin pairs of unlike sex, some 5,000 parents of these twins, and selected siblings of both twins and parents. All twins will initially studied within three months of their 16th birthday, with subsequent follow-up planned for age 18 and, in projected research, again at age 21. The baseline survey, at age 16, will occur when most Finnish adolescents are initiating social drinking; the first follow-up is timed when the twins are leaving home, separating from one another, beginning adult careers or their military service. Questionnaire content includes assessment of drinking habits, attitudes and expectancies toward alcohol, stressful life events, social support, and personality dimensions that are associated with early alcohol abuse. The twins' parents and uncles will be screened for alcohol-related disorders via linkage to the hospital discharge registries to identify adolescent twins at confirmed genetic risk. The research aims are (i) identification of genetic and environmental influences on initiation, continuity, and change in social drinking, (ii) modulation of these influences by age, gender, familial history of alcohol abuse, life events, and change in twins' social contact, and (iii) identification of individual and familial markers for sequencing from adolescent social drinking to adult abuse of alcohol. The revised application proposes broader assessment and behavioral problems associated with alcohol use and new structural modeling analyses for which two expert co-investigators have been added to the project staff.

This application requests support to initiate a research program directed to the familial nature of the use and abuse of alcohol, to assessment of age, gender, and social modulation of genetic influences on drinking during the critical developmental period from mid-adolescent to early adulthood, and to the early identification of familial and behavioral markers among those who are at risk for sustained abuse of alcohol. The research will use a unique resource: The Finnish Twin-Family Cohort, population-based, and linked to a nation-wide death, disease, and insurance registers. We propose a prospective study design in which five consecutive, nation-wide birth cohorts of adolescent twins, their siblings, parents, and selected siblings of both parents will be longitudinally studied. Over the course of a five-year period,> 12,500 members of 2,600 kinships of adolescent twins will be assessed with postal questionnaires. The study population will include > 1,600 pairs of like- sex twins, about 800 twin pairs of unlike sex, some 5,000 parents of these twins, and selected siblings of both twins and parents. All twins will initially studied within three months of their 16th birthday, with subsequent follow-up planned for age 18 and, in projected research, again at age 21. The baseline survey, at age 16, will occur when most Finnish adolescents are initiating social drinking; the first follow-up is timed when the twins are leaving home, separating from one another, beginning adult careers or their military service. Questionnaire content includes assessment of drinking habits, attitudes and expectancies toward alcohol, stressful life events, social support, and personality dimensions that are associated with early alcohol abuse. The twins' parents and uncles will be screened for alcohol-related disorders via linkage to the hospital discharge registries to identify adolescent twins at confirmed genetic risk. The research aims are (i) identification of genetic and environmental influences on initiation, continuity, and change in social drinking, (ii) modulation of these influences by age, gender, familial history of alcohol abuse, life events, and change in twins' social contact, and (iii) identification of individual and familial markers for sequencing from adolescent social drinking to adult abuse of alcohol. The revised application proposes broader assessment and behavioral problems associated with alcohol use and new structural modeling analyses for which two expert co-investigators have been added to the project staff.

This application requests support to initiate a longitudinal study of behavioral precursors of alcoholism in a population of 12-year-old Finnish twin children. Over a five-year period, approximately 6,000 twin children, ascertained from nation-wide birth cohorts, will be assessed, at baseline and biennial follow-up, with self-reports and parental/teacher-ratings. Both parents of all twins will complete questionnaire assessments of their use, tolerance, and dependency on alcohol. From each of four consecutive twin cohorts, two subsamples will be intensively followed-up: 180 twin pairs will be randomly selected, and each random subsample will be supplemented by approximately 70 twin pairs ascertained at elevated risk for the development of alcoholism by baseline screening of their parents. Twins in the two selected subsamples will be rated by classmate peers during in-school exercises that include peer assessments of the twins' closest classroom friends. Parents of random and at-risk subsamples will be interviewed, at local health centers, using relevant sections of Semi- Structured Assessment for Genetics of Alcoholism (SSAGA). At age 14, intensively studied twins will be interviewed with the Adolescent Version of SSAGA. The aims of this research effort are: (i) to evaluate contributions of parental alcoholism and other parental psychopathologies to type and prevalence of behavioral precursors for alcohol abuse observed during mid-childhood and early adolescence; (ii) to assess heterogeneity in pathways to alcoholism by following developmental trajectories of aggressive, anxious, and adaptive behavioral dispositions, modeling genetic and environmental influences on continuity and change over time; (iii) with unique data, from large samples of male/female dizygotic twin pairs, to robustly analyze gene X gender interactions in the expression of alcohol risk; (iv) to test assumptions that the phenotypic covariance of alcohol abuse and temperament reflect common genetic dispositions and shared environmental origins, and explore mediating and moderating effects on that covariance; (v) to assess effects of variation in the timing of psychosexual maturation on onset of alcohol use and the sequential development of abuse; and, (vi) to evaluate influences of parental attitudes and expectations toward alcohol; of parental modeling and parental monitoring; of family structure, support and stress; and of characteristics of peers and residential and school neighborhoods on (twin) children's alcohol expectancies and the onset, development, and familial aggregation of their social drinking patterns. Results will provide a foundation for the continuing study of these twin cohorts as they develop into late adolescence and early adulthood.