Bruce F. Pennington - US grants

The overall goal of this research project is to further elucidate the cognitive deficit or deficits responsible for the reading and spelling difficulties of individuals with familial dyslexia. This project is unique among studies of dyslexia in that the dyslexic subjects are homogeneous with respect to etiology: they have an autosomal dominant form of familial dyslexia which is linked to chromosome 15. Thus they are likely to be both more homogeneous and specific in their phenotype than other dyxlexic populations. Moreover, as in the case of other cognitive disorders (e.g., mental retardation), the identification of an etiologically pure subtype (e.g., Down's Syndrome) has significant long term advantages in terms of both understanding the pathophysiological mechanisms involved and prevention. Since our previous work indicates that the nature of these dyslexics' reading and spelling problems changes with development, the present study will also attemtp to further specify the basis of these developmental changes. The first phase of the investigation will focus on developing experimental paradigms to test competing hypotheses of what the underlying cognitive deficit or deficits are at three different developmental ages: adulthood, 11 to 14 years, and 7 to 10 years. In the second phase, these paradigms will then be applied cross-sectionally to samples of familial dyslexics, their unaffected family members, and non-familial dyslexics in each age group. A third phase will involve a three year longitudinal study of the youngest group in all three categories of subjects. A long-term goal is to use the understanding of the reading and spelling deficits in this particular subtype of dyslexia to improve diagnosis and intervention for other learning disabilities.

DESCRIPTION (Adapted from applicant's abstract): The proposed research is the competitive renewal of an NIMH MERIT award focused on the linguistic phenotype in familial dyslexia. Our earlier work has clarified both the underlying cognitive phenotype and the genetic etiology of familial dyslexia. We propose to extend that work by examining both the phenotypic and genotypic relation between dyslexia (or reading disability--RD) and phonological disorder (PD), which manifest at different ages but exhibit several intriguing commonalities. The two disorders overlap symptomatically in that some prospective studies of children with PD find they later have an elevated rate of RD and in that retrospective studies of children with RD document elevated rates of earlier PD. The underlying cognitive phenotype that is characteristic of RD, a deficit in phoneme awareness, is also found on follow-up in many cases of PD. Finally, there is evidence that each disorder is under genetic influence and that the two disorders are co-familial. In sum, there is evidence for overlap at three levels of analysis: defining symptoms, underlying cognitive processes, and familial etiology. We will test five competing explanations for this overlap: 1) that they are the same disorder in terms of both genetic etiology and cognitive phenotype, but that the symptom manifestations differ depending on severity such that PD + RD is a more severe manifestation than RD alone; 2) that they share a common etiology which acts pleiotropically to produce either PD, RD, or both in a given individual; 3) that PD and RD have distinct etiologies, but share a common cognitive phenotype (cognitive phenocopy hypothesis); 4) that PD and RD have distinct etiologies, but that PD accompanied by specific language impairment develops into a symptom phenocopy of RD (synergy hypothesis); or 5) that PD and RD have distinct etiologies, but co-occur in offspring because of assortment (RD individuals are more likely to mate with PD individuals). We will perform four principal tests to distinguish these hypotheses. Specifically, we will test 1) whether there is a common cognitive phenotype by means of a longitudinal study; 2) whether there is a common genetic etiology by means of a linkage analysis of PD families; 3) whether there is assortment by examining parents of PD and RD children; and 4) how PD, RD, and PD+RD segregate in families.

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to understand the comorbidity between speech sound disorder (SSD) and reading disability (RD). Accomplishing this goal will help us understand the relation between spoken and written language development. Despite their surface differences, it turns out that SSD and RD are co-familial, coheritable, and share a deficit in phonological development. But the comorbidity between SSD and RD is not complete because there are some children with SSD who do not develop RD and some children with RD who never had SSD. Hence, there must also be both etiological and cognitive risk factors that are specific to each disorder, which the proposed research also seeks to identify. We will continue to use molecular methods to specify which genetic risk factors are shared by SSD and RD and which are specific, and we will also examine the contribution of environmental risk and protective factors to these disorders. To increase the power of the molecular analyses, we are recruiting an additional 85 independent sib pairs for a total sample of 150 families and at least 180 sib pairs. To understand which cognitive risk factors are shared by SSD and RD and which are specific, we will complete an ongoing longitudinal study of 111 preschool probands with SSD, and 41 controls similar in age, gender, and SES, adding cross-sectional samples of RD children at both time points: age 5 (before the onset of literacy instruction) and age 8 (early in literacy development). Completing this longitudinal study will allow us to determine how many SSD probands develop RD and to test directly which cognitive deficits are shared by SSD and RD and which are specific at different points in early literacy development.

The focus of the proposed research is continued genotype and phenotype studies of families who demonstrate autosomal dominant transmission of dyslexia. Dyslexia is linked to chromosome 15 markers in some of these families, but not in others, indicating genetic heterogeneity. The specific long-term objectives of this project are (1) to more precisely map the dyslexia locus on chromosome 15 and to evaluate whether there is a second major dyslexia locus on another chromosome in families not linked to chromosome 15; (2) to clarify the development of both the underlying linguistic phenotype and components of the reading process in dyslexics from these families; (3) to test for any phenotypic differences between genotypically different dyslexics; and (4) to determine whether there is continuity in the underlying linguistic phenotype from preschool to adulthood, and, if so, to determine how this underlying deficit affects reading processes at different ages. Because of the unique advantages of developmental studies within dyslexic families with a common etiology, the proposed research will yield a much clearer picture of dyslexic development across the life-span than has previously been possible. Achieving these objectives will lead to a clearer, scientific understanding of the effects of one (or more) major genes on a specific and culturally significant aspect of human cognition. Clinically, such an understanding will form the basis of a well- grounded approach to early identification and treatment of this common developmental disorder. The methodology that is proposed to meet these objectives consists of (1) continued linkage studies of both old and new families in collaboration with Shelley Smith and Bill Kimberling in Omaha; (2) a cross-sectional study of both the underlying linguistic phenotype and the components of the reading process in adolescent and child dyslexics from these families; and (3) a longitudinal study of the underlying linguistic phenotype in preschool children to determine which aspect of this phenotype is most predictive of later dyslexia in these high-risk families.

The overall goals of the proposed research are to achieve a better understanding of both the genetics and the phenotype(s) of developmental dyslexia. Genetic heterogeneity appears to be very likely in dyslexia, but key features of the linguistic phenotype appear to be common across etiologies. Whether certain clinical correlates of dyslexia are part of the phenotype(s) is much less clear. The specific aims of this project are (1) to test alternative models of genetic transmission of dyslexia and to obtain better information about both the transmissible phenotype and genetic parameters important of linkage analysis; (2) to more precisely map the dyslexia locus on chromosome 15 and to confirm or disconfirm a second possible locus on chromosome 6 near the HLA region; (3) to screen the genome for other regions which appear to contribute to the dyslexia phenotype(s); (4) to clarify the development of the underlying linguistic phenotype and components of the reading process; (5) to determine which phonological processing deficits are causal predictors of later familial dyslexia; and (6) to determine whether and how apparent clinical correlates of dyslexia are related to the dyslexia phenotype(s). The methodology that is proposed to meet these objectives consists of (1) segregation analyses using POINTER (Lalouel, et al., 1983) of three large samples of dyslexic families; (2) continued linkage studies of 25 large dyslexic families; (3) a sibling pair linkage study using 100 dyslexic DZ twins pairs; (4) a cross -sectional study of the linguistic phenotype in both family and clinic dyslexics; (5) a longitudinal study of the linguistic precursors of reading in preschool children of either high or low familial risk for dyslexia; and (6) longitudinal, cosegregation, and coheritability analyses of apparent clinical correlates of the dyslexia phenotype. Achieving these objectives will lead to a clearer, neuroscientific understanding of the effects of genes on a specific and culturally significant aspect of human cognition. Clinically, this research will contribute to a well-grounded approach to early identification and treatment of this common developmental disorder.

The overall goal of the proposed research is to use converging methods to better understand the causal relation between RD and its psychiatric correlates particularly ADHD. The specific goals of the proposed research are: 1. To administer measures of attention deficit hyperactivity disorder (ADHD) and executive functions (EFs) to three different populations; a) 50 pairs of MZ and 50 pairs of DZ twins in which at least one member of each pair is reading disabled (RD); b) an independent sample of 50 pairs of MZ and 50 pairs of DZ twins in which at least one member of each pair manifests symptoms of ADHD; and c) a comparison group of 50 pairs of MZ and 50 pairs of DZ twins with no school history of learning disabilities (LDs) or ADHD. 2. To perform a genetic linkage study to identify one or more quantitative trait loci (QTLs) influencing ADHD. 3. To test competing explanations for the association between RD and ADHD using genetic and neuropsychological analyses. 4. To examine the rates and etiology of other psychiatric correlates of RD and ADHD.

The overall goal of the proposed research is to test for genetic and environmental influences on brain structure in reading disability (RD) by performing morphometric analyses of MRI scans collected from RD and non-RD twin pairs. The specific goals of the proposed research are: 1.) To collect MRI scans from 20 twin pairs a year. When combined with the current sample, this will result in a total sample of 80 monozygotic (MZ) and 80 dizygotic (DZ) pairs in which at least one member of each pair will be reading disabled (RD) and 20 DZ pairs in which neither member will be RD. 2.) To perform state-of-the-art morphometric analyses, including cortical parcellation analyses, of these MRI scans targeting structures previously implicated in RD. These morphometric analyses will be performed without knowledge of subjects' diagnosis, relation, or zygosity. 3.) To conduct multivariate behavior genetic analyses of a.) the genetic and environmental components of variation in these morphometric measures and b.) their phenotypic and etiologic relations with behavioral measures. These analyses will be both confirmatory - by testing current strong hypotheses about brain-behavior relations in RD - and exploratory. 4.) To test whether the gene (s) influencing RD also influence brain structures which differentiate individuals with RD from controls. These analyses will use the methods in Research Project 4. 5.) To address basic issues in the new field of in vivo measurement of brain morphometry, such as relations among various brain structures and their relations to external variables, such as sex, age, and cognitive abilities.

disease /disorder proneness /risk; phenylketonuria

In contrast to several other mental retardation syndromes, the neuropsychology of Down Syndrome is relatively unexplored. The proposed research will fills gap in existing knowledge by testing the functional status of three neural systems particularly at risk in DS: the prefrontal cortex, hippocampus, and cerebellum. We will examine these three neuropsychological domains in a cross-sectional study of two age cohorts of individuals with DS (n=36 each) compared to two control groups, 1) younger normally developing children matched on MA, and 2) CA and MA matched children with non-DS mental retardation. Our component will provide a target phenotype for our colleagues working with mouse models, which will help them isolate the specific genetic determinants of the neural bases of this form of mental retardation.

The overall goal of the proposed research is to test the internal and external validity of subtypes of ADHD using converging methods. To accomplish these objectives as part of our ongoing study, we will administer a batter of neuropsychological and psychiatric measures to samples of RD, ADHD, and control twin pairs (50 MZ and 50 DZ pairs in each group) and their siblings. The reliability and internal validity of the ADHD subtypes will be tested by examining inter-rater agreement and test-retest reliability and conducting factor and cluster analyses of individual symptoms. Diagnostic and discriminant validity of the subtypes will be tested by comparing subtypes on measures of functional impairment and other clinical correlates. Etiological relations among the subtypes will be tested using multiple regression analyses of twin data and molecular genetic linkage and association methods, and the cognitive relations among the subtypes will be tested with neuropsychological measures. The neuropsychological battery is designed to test further the executive deficit hypotheses of ADHD by pitting it against competing hypotheses that suggest ADHD is attributable to a deficit in motivation, arousal regulation, or response modulation.

AD/HD; ADHD; Attention deficit hyperactivity disorder; Attention-Deficit Disorder, Predominantly Hyperactive-Impulsive Type; Biological; Candidate Disease Gene; Candidate Gene; Causality; Childhood; Cognitive; Collaborations; Comorbidity; Complex; Comprehension; DNA; DSM-IV; DSM4; Data; Deoxyribonucleic Acid; Diagnostic; Diagnostic and Statistical Manual of Mental Disorders, 4th edition; Diagnostic and Statistical Manual of Mental Disorders-IV; Dimensions; Disabled Persons; Disabled Population; Disease; Disorder; Dizygotic Twins; Etiology; Functional impairment; Genes; Goals; Handicapped; History; Hyperactivity Disorder NOS; Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type; Hyperkinetic Syndrome; Interview; Linkage Analysis; Measures; Methods; Modeling; Monozygotic twins; Neurocognitive; Neuropsychologic Tests; Neuropsychological Tests; Neuropsychologies; Neuropsychology; Parents; People with Disabilities; Persons with Disabilities; Predisposition; Process; Psychometric; Psychometrics; QTL; Quantitative Trait Loci; R01 Mechanism; R01 Program; RPG; Rate; Reading; Reading Disabilities; Reading disability; Recording of previous events; Research; Research Grants; Research Project Grants; Research Projects; Research Projects, R-Series; Risk Factors; Sampling; Schools; Siblings; Susceptibility; Symptoms; Testing; Twin Multiple Birth; Twins; Twins, Dizygotic; Twins, Fraternal; Twins, Identical; attention deficit hyperactive disorder; disabled; disabled people; disease causation; disease classification; disease etiology; disease/disorder; disease/disorder classification; disease/disorder etiology; disorder classification; disorder etiology; executive control; executive function; family based linkage study; frontal cortex; frontal lobe; functional disability; genetic linkage analyses; genetic linkage analysis; linkage analyses; member; neuropsychologic; neuropsychological; nosology; pediatric; processing speed; teacher; theories

Research Project III Summary Building on extensive past research by Project III on the comorbidity of reading disability (RD) and ADHD, the proposed research will extend those methods and concepts to understanding the comorbidities among less-studied complex LDs, and their comorbidities with ADHD and with RD. Project III will use multiple methods of analysis to examine how component cognitive skills, including executive functions (EFs), contribute to these comorbidities. Previous research has demonstrated that ADHD is comorbid with each of these less-studied LDs, including poor reading comprehension, poor written language, and poor math problem solving ability, and considerable prior research indicates a role for EFs in these disorders. Proficiency in these academic skills requires not only mastery of prerequisite basic skills, but also higher level-thinking skills, such as oral language comprehension and EFs. Project III will explicitly test versions of this interactive model of these three complex LDs in collaboration with Projects II and V. So the goal of Project III is to gain a comprehensive understanding ofthe comorbidities among these three complex LDs and their comorbidities with both ADHD and RD. In collaboration with Project I, Project III will also continue ongoing work on the comorbidity between dyslexia (RD) and ADHD. Project III will test these comorbidities at both the cognitive and etiological levels of analysis. It will also test whether GxE interactions are part ofthe etiology of these disorders and their comorbidities. Even though there is considerable evidence for shared cognitive and genetic risk factors across these disorders, their relations have not been previously examined in the same sample.

PROJECT SUMMARY/ABSTRACT Comorbidity is pervasive among the learning disabilities (LDs) (comorbidity rates of 25-50%) and is a key predictor of academic and functional outcomes, yet little is known about the cognitive mechanisms that increase a child?s risk for multiple disorders. This project proposes a multiple deficit model of LDs where shared cognitive risk factors contribute to comorbidity of reading and math (basic and higher-order skills) and ADHD. The overall goal of this project is to use converging methods, including latent modeling, experimental methods, and behavioral genetics, to identify the role of shared cognitive risk factors in the comorbidity of LDs and ADHD. Potential shared cognitive deficits between learning disabilities and ADHD include processing speed (PS), executive functions (EFs), and specific domains of implicit learning. Although these factors have each been examined in LDs individually, this is the first study to assess the impact of these related constructs on comorbidity across LDs. One challenge with the PS construct is the ?task impurity? of the measures. To address this concern, we will systematically examine 4 theoretical models (some non-exclusive) about the role of PS in LDs and ADHD: (1) PS is reducible to cognitive g, (2) PS is reducible to EF, (3) PS is a domain- general factor, (4) PS has content-specific components that are associated with specific academic skills. Aim 1 will examine these 4 models by introducing new experimental PS tasks and leveraging existing data with advanced latent models of the shared and unique variance among the constructs. Another potential shared cognitive risk factor among learning disabilities are deficits in implicit learning, specifically the subdomains of procedural learning and statistical learning, which we have not yet studied in this sample. Aim 1 will include new measures of procedural (motor-based) and statistical (language-based) learning. This will be the first study to examine the association of these constructs with multiple LDs and ADHD. Because this LD center employs a genetically-sensitive twin design, we will be able to draw genetic inferences from the best-fitting cognitive models. In Aim 2, we will determine whether shared cognitive risk factors also share genetic relationships with the comorbid LDs. The population of bilingual youth is growing exponentially in the US, yet we still know very little about academic development in this population. In Aim 3, we plan to test the best-fitting multiple deficit model from Aim 1 in a sample of bilingual, Hispanic youth. This analysis will be an important test of the universality of the multiple deficit model where points of divergence will have important clinical implications. The focus of this project on identifying and dissecting shared cognitive risk factors for LDs and ADHD has clinical relevance for assessment of comorbidity risk and for novel treatment targets that may impact generalized cognitive risk mechanisms.