John C. DeFries - US grants

The primary objective of the Colorado Adoption Project--a longitudinal, prospective adoption study funded by NICHD from 1977 through 1993--is to assess genetic and environmental influences on individual differences in behavioral development among children. The study includes biological parents who relinquished their children for adoption at birth, parents who adopted these children, matched 'control' (nonadoptive) parents, and the children (probands and younger siblings) in these families. Adults were administered a 3-hour battery of behavioral tests that included measures of the major factors of cognitive abilities and personality; information pertaining to family background, common medical and behavioral problems, interests and talents, and frequently used drugs have also been obtained. For the children, the assessments employ standard tests of cognitive and language development, personality/temperament, motor development, and health. Environmental assessments in the adoptive and control homes are emphasized. The adopted and control probands and their younger siblings are studied in their homes at 1, 2, 3, and 4; in the laboratory at 7 and 12; and via telephone interviews at 9, 10, and 11. The proposed continuation of HD-10333 will culminate the assessment of children in the Colorado Adoption Project during late adolescence. The adopted and control children will be interviewed at 13, 14, and 15 years of age. At 16 years of age, they will be administered the same test battery that their parents completed over a decade and a half earlier. During years 17-21 of HD-10333, the numbers of adopted and control children who will have been studied at 13, 14, 15, and 16 years, respectively, are 584, 561, 474, and 449. Moreover, 180 older siblings of these children will have been administered the adult-test battery. Of the various methods available to study the origins of individual differences in behavioral development, the full adoption design employed in the Colorado Adoption Project is the most powerful. The proposed continuation of HD-10333, which will make it possible to reap the final harvest from this landmark study, will substantially advance basic research in child development and is likely to have important implications for child-rearing practices, education, and mental health.

The long-range objectives of this program project are the identification, characterization, and validation of distinct subtypes or dimensions of reading disability. To accomplish these objectives during budget periods 10-14, a test battery that includes measures of cognitive abilities and of reading and language processes will be administered to a total of 1,000 subjects, including identical and fraternal twin pairs in which at least one twin is reading disable, parents of these twins, members of identical and fraternal twin families in which the children are normal readers, and nontwin reading-disabled and control children for whom extensive longitudinal data have been collected. Resulting twin and family data will be used to validate alternative typologies and to conduct genetic analyses. A survey of immune disorders and laterality will also be undertaken in the twin sample, and subsets will be evaluated for immunology and neuroanatomical differences using autoantibody assays and magnetic resonance imaging. A group of identical twins will also be administered differential training in phonological coding to assess subtype-by-treatment interaction. Concurrently, a linkage analysis will be employed to test the hypothesis that a form of reading disability is due to an autosomal dominant gene located on chromosome 15.

A Drug Abuse Research Center (DARC) is proposed to be established at the Institute for Behavioral Genetics (IBG), University of Colorado, Boulder. Faculty members of IBG are nationally and internationally known for their research in quantitative genetics of human behavioral characters (including cognition, reading disability, personality development, and responses to alcohol) and in behavioral pharmacogenetics. Thus, establishment of a DARC at IBG would facilitate a multidisciplinary approach to the problem of vulnerability to drug abuse. The Research Components proposed include (1) quantitative genetic analyses of the cigarette withdrawal syndrome; (2) a study of the families of severe substance-abusing teenagers; 3) assessment of the tension-reduction hypothesis of nicotine's action and development of animal models of cigarette withdrawal; (4) studies of the effects of amphetamine, cocaine, ethanol, and morphine on neurotensin and dopamine levels in mesolimbic and mesocortical dopaminergic pathways in 8 strains of mice; (5) application of genetic strategies to delineate predispositional factors for cocaine hepatotoxicity, and studies of their potential application to cocaine use and toxicity in humans: (6) studies of the development of tolerance and physical dependence to cocaine and amphetamine in lines of mice selected for high or low open-field activity, and the effects of these drugs on learning and memory in these lines; (7) bi-directional selective breeding to produce replicate lines of mice which differ in responses to nicotine, and to cocaine; and (8) determination of the relationship between cocaine initial sensitivity, tolerance or sensitization acquisition, and withdrawal severity in inbred strains of mice. The investigators will benefit by sharing scientific resources such as the specific-pathogen-free mouse facility and twin/adoptee registers, and from comparing results derived from a common database of inbred strains and selected lines of mice to those derived from human subjects. Results obtained from research conducted within the proposed DARC should contribute to a better understanding of the etiology of individual differences in drug- related behaviors, and should add a valuable knowledge base for clinical intervention strategies for the individual.

biomedical equipment purchase;

The long-range objective of the Colorado Learning Disabilities Research Center are the identification, characterization, validation and amelioration of etiologically distinct subtypes or dimensions of learning disabilities. To accomplish these objectives, test batteries that include psychometric measures of cognitive and academic abilities (Research Project 2), reading, language and perceptual processes (Research Project 3), and ADHD and executive functions (Research Project 3 will be administered to a sample of 50 pairs of identical twins and 50 pairs of fraternal twin in which at least one member of each pair is reading disabled, to an independent sample of 50 pairs of identical twins and 50 pairs of fraternal twins in which at least one member of each pair has ADHD, and to a comparison group of 50 pairs of identical twins and 50 pairs of fraternal twins with no school history of learning disabilities or ADHD. Resulting data will be used to asses the genetic and environmental etiologies of reading deficits and ADHD, as well as their covariation with measures of mathematics performance, phonological and orthographic coding, and executive functions. In order to map major genes and/or quantitative trait loci that influence learning disabilities, blood samples will be drawn from fraternal twin pairs and subjected to genetic linkage analyses (Research Project 4). Concurrently, a longitudinal at-risk sample of 100 children will be administered differential computer-based remediation to test for possible subtype-by-treatment interactions (Research Project 5). In order to assess genetic and environmental correlates of neurobiological factors and reading deficits, MRI scans will be obtained from 100 twin pairs in which at least one member of each pair is reading disabled and from 25 pairs of control twin pairs and then subjected to state-of-the-art morphometric analyses (Research Project 6). An administrative core unit will be responsible for coordinating the activities of the six research projects; maintaining communication among the participating investigators; ascertaining and scheduling subjects; obtaining questionnaire data from families of twins; obtaining blood samples from families of fraternal twins; compiling and managing a master file of combined data sets; and administering the Center budget and other fiscal matters.

biomedical equipment purchase;

The long-range objectives of Research Project 1 are the identification, characterization, and validation of etiologically distinct subtypes or dimensions of learning disabilities. To accomplish these objectives, an extensive psychometric test battery will be administered to a sample of 50 pairs of identical twins and 50 pairs of fraternal twins in which at least one member of each pair is reading disabled, to an independent sample of 50 pairs of identical twins and 50 pairs of fraternal twins in which at least one member of each pair has ADHD, and to a comparison sample of 50 pairs of identical twins and 50 pairs of fraternal twins with a school history of no significant reading deficits or behavioral problems. In collaboration with investigators from Research Projects 2-6, resulting data will be used to assess the genetic and environmental etiologies of reading deficits and ADHD, as well as their covariation with measures of reading, language and perceptual processes, mathematics performance, executive functions, and brain morphometry. Reading performance data will also be used to test hypotheses of differential etiology as a function of age, gender, and cognitive ability, and to test the hypothesis that the etiology of deviant scores differs from that of individual differences within the normal range.

DESCRIPTION: Objective: The proposed research aims to build knowledge about family determinants of children's social and economic well being as children come into their own and make the transition to adulthood. Specific hypotheses address familial influences on educational attainment, family determinants of union- and family-formation choices of young adults, and how the quality of early family relationships shapes adult child-parent relationships. Methods: The investigators address these questions in the context of an adoption design which offers an opportunity to carry out especially powerful tests of socialization and social-psychological theories. The adoption design is 'powerful' because it allows them to test family determinants of children's outcomes independently of genetic influences. They capitalize on the resources of the Colorado Adoption Project (CAP), a long-term, longitudinal adoption study of 245 adoptive families and 245 nonadoptive families. The CAP children, their siblings, and their home environments have been assessed repeatedly since infancy using a broad, multivariate battery of social, environmental, and behavioral measures. The investigators propose to interview the probands and their siblings as they reach adulthood. Significance: The proposed research is innovative, both in the fields of behavioral genetics and in social demography, in that it brings behavioral genetic methods to bear 1) on sociological and social-demographic phenomena and 2) on the study of life-course developmental process. The marriage of behavioral genetics and social demography promises to advance understanding of how family factors influence children's life chances and to enrich socializ-ation models of life-course development.

A genetic contribution to anxiety-related disorders is not in doubt, but the nature of that contribution is still poorly understood. We propose to conduct a quantitative trait loci (QTL) study of fear- related/emotional behavior in the mouse as a first step to understanding possible genetic mechanisms in humans. An extensive test battery will be used to characterize fear-related behaviors in the mice and to identify potential confounds with general activity, photophobia, and thigmotaxis. We will use both simple univariate QTL mapping techniques and more recent multivariate mapping techniques to locate QTLs in F2 mice. These methods have been remarkably successful in mapping QTLs in plants and more recently in animal studies. The studies outlined in this proposal will use an inbred strain of mice that was derived from lines that were selectively bred for what may be fear- related behaviors. The mouse stains (developed by DeFries) were selectively bred for differences in open-field activity; two high (H1 and H2) and two low (L1 and L2) strains were developed. The H-L strains also differ in open-field defecation (L more H). F2 hybrids will be developed from L1 - H1 crosses and L2-H2 crosses. The F2 mice will be evaluated for activity in home cage and several measures of fear- related and depressive behaviors. Approximately 800 F2 animals will be scored in each cross (1600 animals total) and DNA from these same animals will be screened for polymorphisms using 84 microsatellites. The strategy of testing the replicability of the QLT method using two crosses derived from the mouse should serve as a rigorous test of the QTL methodology and could also facilitate the identification of fear- related genes in humans.

The long-range objectives of Research Project I are the identification, characterization, and validation of etiologically distinct subtypes or dimensions of learning disabilities. To accomplish these objectives, an extensive psychometric test battery will be administered to a sample of 50 pairs of identical twins and 50 pairs of fraternal twins in which at least one member of each pair is reading disabled, to an independent sample of 50 pairs of identical twins and 5o pairs of fraternal twins in which at least one member of each pair has ADHD, to a comparison sample of 50 pairs of identical twins and 50 pairs of fraternal twins with no school history of reading deficits or ADHD, and to the siblings of all twin pairs. In collaboration with investigators from Research Projects II-IV, resulting data will be used to assess the genetic and environmental etiologies of reading deficits, ADHD, and their co-morbidity, as well as their co- variation with measures of other psychopathology, reading, language and perceptual processes, mathematics performance and executive functions. These data will also be used to test noel hypotheses of differential etiology of reading difficulties as a function of ADHD dimensions or subtypes, age, gender, and cognitive ability, and to assess the hypothesis that the etiology of deviant scores differ from that of individual differences within the normal range.