Erik G. Willcutt - US grants

DESCRIPTION (Adapted from Applicant's Abstract): The proposed research will utilize behavioral and molecular genetic techniques to examine the etiology of DSM-IV Attention Deficit/Hyperactivity Disorder (ADHD) in a sample of 100 8-13 year old twins selected because at least one twin meets the criteria for ADHD. Univariate behavioral genetic models will be utilized to estimate the genetic and environmental components of the etiology of the subtypes of ADHD. In addition, bivariate behavior genetic analyses will be utilized to directly examine the influence of common genes on the three proposed subtypes and the etiology of any observed psychiatric comorbidity with ADHD. DNA samples will be obtained from all DZ twins and their families. Association analyses such as the Transmission Disequilibrium Test will be utilized to test whether any component of the ADHD phenotype is significantly associated with any of several theoretically plausible candidate genes. In addition, a bivariate interval mapping linkage analysis will be utilized in a sample of individuals already typed for the relevant markers to test whether a previously mapped quantitative trait locus for reading disability on chromosome 6 is also etiologically related to ADHD.

The proposed project will test the internal and external validity of DSM-IV attention- deficit/hyperactivity disorder in an ethnically diverse population that includes a large proportion of African American and Hispanic children. Parent and teacher ratings of ADHD will be obtained for a large community sample of children in the Denver metropolitan area. The proposed study will provide the first estimates of the prevalence of DSM-IV ADHD among African American and Hispanic children, as well as the prevalence of each of the three diagnostic subtypes of DSM-IV ADHD. Several competing explanations for ethnic differences in the prevalence of ADHD will be tested, including rater bias and response to prejudice. Exploratory and confirmatory factor analysis will be used to test if the internal structure of the diagnosis varies as a function of ethnicity. Demographic variables such as socioeconomics status, location of residence, exposure to environmental stressors, and rater ethnicity will be assessed to test if these variables account for differences in the ratings of children from different ethnic groups. Measures of functional impairment and comorbid psychopathology will be administered to test if children with ADHD from different ethnic groups exhibit differences in these domains. In order to assess the etiology of ADHD in African American children, more extensive assessments will be conducted with 200 probands with ADHD and 200 comparison probands selected from the overall African American sample. Parental ADHD will be assessed to test if ADHD is significantly familial in an African American population, and data will be obtained regarding difficulties during pregnancy or delivery to test if perinatal complications are associated with ADHD. DNA samples will be obtained from all probands, their parents, and the biological sibling closest in age to the proband. Case- control and sib-pair comparisons, and the transmission disequilibrium test will be used to conduct the first for genetic association between several theoretically plausible candidates genes and ADHD in an AA sample.

DESCRIPTION (provided by applicant): The proposed project will test the internal and external validity of subtypes of DSM-IV ADHD using multiple converging methods. To accomplish these objectives, measures of ADHD symptoms, functional impairment, intellectual/academic achievement, other psychopathology, and neuropsychological functioning will be administered to the following groups selected from an initial pool of 11,000 non-referred children: 150 probands with the combined subtype, 150 with the hyperactive/impulsive subtype, 150 with the inattentive subtype who also exhibit significant symptoms of sluggish cognitive tempo (SCT), and 150 with the inattentive subtype without significant SCT symptoms, as well as comparison samples of 150 children with significant elevations of SCT who do not meet criteria for any ADHD subtype and 150 children without ADHD or significant SCT symptoms. Reliability and internal validity of the DSM-IV subtypes will be tested by examining inter-rater agreement and conducting exploratory and confirmatory factor and cluster analyses. Longitudinal follow-up measures will be obtained annually to facilitate analyses of the temporal stability and developmental course of the DSM-IV symptoms and subtypes. The diagnostic validity of the DSM-IV subtypes will be examined by testing if each subtype is associated with significant impairment in other domains of functioning. Discriminant validity among the subtypes will be evaluated by comparing subtypes on measures of functional impairment and other clinical correlates, and by testing if symptoms of SCT identify a diagnostically meaningful subset of individuals within the inattentive subtype. To examine both genetic and non-genetic etiological factors, pre/perinatal complications will be assessed and DNA samples will be obtained from all probands, their parents, and the biological sibling closest in age to the proband, facilitating a direct test for differential etiology of ADHD subtypes using genetic linkage and association analyses. Finally, all participants will complete an extensive battery of neurocognitive measures to test for differential performance among the subtypes on cognitive/attentional measures and the contribution of SOT to these differences. It is expected that the use of a large community sample, a longitudinal assessment, an etiologically informative design, and a broad battery of neurocognitive measures will provide important new information regarding the optimal nosology of ADHD.

DESCRIPTION (provided by applicant): The primary goal of the proposed study is to assess the genetic etiology of reading disability (RD) and comorbid Attention-Deficit/Hyperactivity Disorder (ADHD), the two most prevalent disorders of childhood. To accomplish this goal, an extensive psychometric test battery, including the WISC-IV, tests of reading performance and related cognitive processes, and parent and teacher ratings of ADHD, will be administered to a sample of 1,650 children from 600 families in which at least one of two or more siblings has a school history of reading difficulties. DNA will be isolated from blood or buccal cell samples obtained from all siblings and both biological parents, and each sample will be genotyped using a procedure that provides genotypes for over 10,000 single-nucleotide polymorphisms in a single assay. These extensive phenotypic and genotypic data will be used to accomplish three goals. First, a genome scan will be conducted in the largest sample of sibling pairs ascertained for RD that has been collected to date. This analysis will attempt to replicate the localization of quantitative trait loci (QTLs) for RD that have been reported in previous studies, and is also expected to reveal new QTLs that have not been detected in previous genome scans. Second, bivariate linkage analyses will be employed to conduct the first genome-wide scan for QTLs with pleiotropic effects on RD and ADHD. Finally, exploratory analyses will be conducted to capitalize on other aspects of the rich phenotypic dataset, including a univariate genome-wide scan for DSM-IV ADHD in this enriched sample of siblings ascertained for reading difficulties.

DESCRIPTION (provided by applicant): Reading disability (RD), math disability (MD), and attention-deficit/hyperactivity disorder (ADHD) are common disorders of childhood that frequently co-occur, but the developmental etiology of this comorbidity is largely unknown. The proposed project is an extension of the Western Reserve Reading and Math Project and the International Longitudinal Twin Study of Early Reading Development, two longitudinal twin studies that have followed population-based samples of twins since preschool. The twins will complete an extensive battery of measures of reading, math, ADHD, and neuropsychological functioning at the end of ninth grade. These measures will provide important new information regarding the developmental etiology of word reading and more complex reading fluency and comprehension, the developmental stability of DSM-IV symptom dimensions and subtypes of ADHD, and the longitudinal and cross-sectional etiology of covariance between individual differences and extreme scores on measures of reading, math, and ADHD symptoms. The extensive battery of neuropsychological measures will be used to test which neuropsychological functions are uniquely associated with RD, ADHD, or MD and which are shared risk factors across two or more of these domains, and multivariate twin analyses will be conducted to test the etiology of these associations. PUBLIC HEALTH RELEVANCE: Reading disability (RD), math disability (MD), and attention-deficit/hyperactivity disorder (ADHD) are common disorders of childhood that often co-occur due to unknown causes. This study will administer measures of neuropsychological functioning to two large longitudinal studies of twins to assess the genetic, environmental, and neuropsychological factors that lead to stability and change in each disorder and the specific factors that lead to their frequent co-occurrence.

PROJECT SUMMARY CORE A: ADMINISTRATIVE CORE All research projects and Cores will benefit from the services provided by the Administrative Core. The Administrative Core will be responsible for the overall operation and coordination of the CLDRC, including both scientific and administrative activities. The Administrative Core will be responsible for ascertainment of all new participants for the Research Projects, including 250 new twin pairs in which at least one twin exhibits significant learning or attentional difficulties, and 100 twin pairs in which neither twin exhibits any difficulty with learning or attention. In parallel, Core staff will recruit a separate sample of 100 bilingual Hispanic adolescents who participated in an earlier study of reading difficulties by CLDRC investigators, providing a unique opportunity to assess the manifestation and developmental outcome of RD in this understudied population. The Administrative Core will also supervise the implementation of data sharing and publication plans; monitor and mitigate known and emergent risks to the Center objectives, and evaluate the explicit benchmarks that will be used to measure the success of the Center. Finally, the Administrative Core will invite and coordinate the involvement of the External Scientific Advisory Board.

PROJECT SUMMARY CORE C: DATA CORE The overall objective of the Data Core is to support all aspects of data collection, verification, consolidation, documentation, and analysis by all CLDRC investigators and our collaborators. Support from the Data Core will enable all CLDRC investigators to take advantage of the rich datasets generated by the CLDRC for innovative analyses of all aspects of learning disabilities (LDs) and related difficulties such as attention- deficit/hyperactivity disorder (ADHD). The Data Core and the overall collaborative structure of the CLDRC provide a unique opportunity for interdisciplinary analyses using data from twin pairs, multigenerational families, neuropsychological measures, neuroimaging methods, and molecular genetics. Further, the infrastructure provided by the Data Core will facilitate the broader impact of the CLDRC by encouraging new synergistic collaborations with investigators outside the Center, and by using technological resources to coordinate a monthly CLDRC webinar series that will provide didactic presentations by all CLDRC investigators on specific data analytic procedures and broader issues around study design.

PROJECT SUMMARY/ABSTRACT The Colorado Learning Disabilities Research Center (CLDRC) is a long-standing interdisciplinary, multisite research program that investigates the genetic and environmental etiologies, neurobiology, neuropsychology, classification, and outcomes of learning disabilities (LDs) and related disorders such as attention/deficit- hyperactivity disorder (ADHD). The overarching long-term goal of the CLDRC is to develop and refine a comprehensive neurodevelopmental and neurobiological model of LDs and related disorders, then to use that model to inform early screening and identification to guide prevention and treatment. Results from the CLDRC will facilitate refinements to theoretical models and improve classification of learning disabilities (LDs) and lead to important improvements in neural models of LDs and related disorders, including the cognitive correlates of LDs in the understudied population of bilingual learners. In combination with the results from the other projects, the molecular genetic analyses in Project IV will provide key information to develop and refine etiological models of the specific genetic and environmental risk factors that contribute to the development of LDs. Of similar importance to these research objectives are our related aims regarding the effective dissemination of our results. In addition to our ongoing efforts to publish our result for the scientific community, the Engagement Core will support efforts to translate and disseminate results from the CLDRC to a broader audiences of practitioners, educators, and individuals with learning disabilities. The CLDRC infrastructure also provides an unprecedented opportunity for interdisciplinary mentorship and project-embedded career enhancement opportunities for the next generation of LD investigators. We will continue to support these opportunities during the next five years through individual training plans, a new CLDRC webinar series, and the CLDRC Pilot Project Program, helping to ensure that the developing scholars in the CLDRC are highly competitive for positions in top-tier research universities when they leave our laboratories and training programs. The most distal long-term research objective of the CLDRC is the development of a comprehensive model of LDs that is based on a complete understanding of LDs at the genetic, environmental, neurobiological, cognitive, behavioral, and instructional levels of analysis. This is a daunting challenge that cannot be overcome by a single scientist or research lab working in isolation. Instead, this work will require the successful integration of diverse literatures, scientific approaches, and analytical strategies. The ongoing and long-term objective of the CLDRC is to continue provide a place where this integration can occur to promote interdisciplinary LD research and to develop the next generation of interdisciplinary scientists and practitioners.

PROJECT SUMMARY/ABSTRACT CORE B: ENGAGEMENT CORE Dissemination and career-enhancing opportunities are the unifying themes of the Engagement Core. A first primary objective of the Engagement Core is to facilitate the dissemination of knowledge gained in the CLDRC research program to a diverse range of audiences, including scientific communities, clinical practitioners, educators, and the general public, including individuals with learning disabilities and their families. The second major objective of the Core is to provide project-embedded career-enhancing opportunities for CLDRC mentees, early career investigators, and established investigators who are new to the field of learning disabilities.These opportunities will be provided by developing individualized mentorship plans, providing infrastructure to support dissemination, and facilitating interactions between new investigators and more senior investigators in the field of LD. Finally, the CLDRC Pilot Project Program will provide a unique opportunity for promising predoctoral, postdoctoral, or early-stage independent investigators to obtain independent funding to collect preliminary data that may help to launch their research career.

PROJECT SUMMARY/ABSTRACT PROJECT I: LEARNING DIFFICULTIES IN READING, WRITING, AND MATHEMATICS AND THEIR CO-OCCURRENCE WITH ADHD: ETIOLOGY, NEUROPSYCHOLOGY, AND FUNCTIONAL OUTCOMES The overall goal of Project I is to examine the relations among all dimensions of learning disabilities and ADHD at the phenotypic, etiological, and developmental levels of analysis and to begin to test these relations in historically understudied and underserved populations. The first primary objective of Project I is to conduct an etiologically-informative study of all aspects of learning disabilities in reading (RD), math (MD), and writing (WD), along with the etiology of covariance among these dimensions of academic difficulties and symptoms of attention-deficit/hyperactivity disorder (ADHD) and the related but distinct dimension of attentional functioning called sluggish cognitive tempo. Tests of basic and higher-order dimensions of reading (word reading, reading fluency, and reading comprehension), math (math calculations, math fluency, and math reasoning), and writing (handwriting, spelling, grammar, and written content) will be administered to a sample of 250 twin pairs between 8 and 12 years of age in which at least one twin has a school history of learning and/or attentional difficulties, along with a comparison sample of 100 twin pairs without learning or attentional difficulties. These data will then be combined with twin pairs tested during the current and previous funding period of the CLDRC to provide sufficient statistical power to test competing models of the phenotypic and etiological structure of all aspects of learning disabilities (LDs). Results of these models will provide a foundation for synergistic collaborative analyses that examine the relations between the latent measures of learning difficulties that are identified and measures of processing speed and executive functions (Project I and II), structural and functional neuroimaging phenotypes (Project III), and molecular genetic risk factors (Project IV). In addition, Project I will conduct include two longitudinal followup studies. In the first study approximately 180 pairs of twins from the CLDRC and an independent sample of 100 bilingual (English and Spanish) Hispanic adolescents with and without RD will complete a streamlined version of the Project I and Project II test batteries approximately five years after they were first tested. The second longitudinal study will administer an online battery of outcome measures to over 1,200 pairs of young adult twins who previously participated in the CLDRC or one of our ongoing longitudinal twin studies of unselected samples in Colorado or Ohio, providing a cost-effective assessment of important longer-term developmental outcomes of LDs.