Robert Plomin - US grants

Little is known about the etiology of individual differences in psychological development during middle childhood, an era marked by changes in cognitive and social behavior nearly as dramatic as those seen during the transition from infancy to early childhood or during adolescence. The proposed research will apply the most powerful quantitative (biometrical) genetic methodology, the "full" adoption design in which data are collected from both birth and adoptive parents, to the study of psychological development in 7-year-olds. The sample is unique: over 400 adopted and matched nonadopted children who previously have been studied in their homes at 1, 2, 3, and 4 years of age using an extensive set of psychological and environmental assessments. The birth parents and adoptive parents of the adoptees and the parents of the nonadopted children have been administered a 3-hour battery of psychological measures. The proposed 5-year project will provide for testing the 7-year-old adopted and nonadopted children on a multidimensional battery of psychological measures including general and specific cognitive abilities, communicative skills, school achievement, temperament, behavioral problems, motoric development, and social interaction. The project will capitalize on the potent design and the extensive data set previously collected as part of the Colorado Adoption Project in applying multivariate, longitudinal, and quatitative genetic analyses to data obtained during the important developmental period marked by the beginning of formal schooling. The results of these analyses, which will substantially advance our understanding of the etiology of individual differences in functioning during this critical epoch, are likely to have important implications for childrearing, education, and mental health.

General cognitive ability ("g") is one of the most heritable behavioral traits. The present application requests renewal (Years 07-09) of the first study (HD27694) attempting to identify some of the specific genes (quantitative trait loci, QTLs) responsible for this heritability. The study uses an allelic association strategy with extreme selected groups in order to achieve the statistical power needed to identify QTLs of small effect size. The first grant (Years 01-03) established samples of 51 high "g" subjects (2SD) at least two standard deviations above the mean (e.g., IQ scores greater than 130) and 51 average "g" control subjects. The current grant (Years 04-06) adds samples of 50 super-high "g" subjects (4SD), 50 very high "g" subjects especially high in verbal ability (3SD- verbal), 50 very high "g" subjects especially high in math (3SD-math), and 50 additional average "g" control subjects. Permanent cell lines are established for all 300 subjects in order to create a permanent resource for molecular genetic analyses of cognitive ability. The proposed three-year project will capitalize on this NICHD investment. We will conduct the first systematic genome scan for allelic association using an exciting new DNA pooling technique developed as part of the current grant. Specifically, the efficiency of DNA pooling will make it possible to genotype 3500 DNA markers at roughly 1 cM intervals throughout the genome for the combined samples of 200 high "g" subjects and 100 control subjects. Most QTL associations that account for as little as 2 percent of the variation in "g" in the population can be detected while guarding against false positives (p lesser then .0001). The largest associations will be individually genotyped and tested in the four subgroups for a linear relationship predicted by our QTL model for "g": 4SD more then 3SD-verbal =3SD-math more then 2SD. Identifying QTLs will carve out handholds in the climb towards understanding neurophysiological pathways between genes and cognitive development.

DESCRIPTION (provided by applicant): The proposed 4-year project will be the first to investigate the effects of measured school environments on cognitive development and academic achievement using a genetically sensitive design. The proposed research will test the hypothesis that genes play a part in mediating the effects of the school environment on educationally relevant behaviors, that is, that children actively select, modify and create environments that are correlated with their genetic propensities. It is also hypothesized that educational influences on cognitive development and academic achievement involve non-shared as well as shared environment. That is, even twins in the same classroom experience different educational environments and these nons-hared environments affect educational outcomes. The project will capitalize on a large twin study of behavioral development in childhood in which 7500 twin pairs born in 1994-96 have been assessed at 2, 3, 4 and 7 years on measures of cognition, language and behavior problems. We plan to assess each child's school and classroom environments at 10 years of age as perceived by the children themselves, as well as their parents and teachers. We will also assess cognitive development and academic achievement in order to test the hypothesis that school environments and their relationship to educational outcomes are in part mediated by genetics. The significance of finding genetic influence on educational experiences and their association with educational outcomes comes from bridging the gulf between the fields of education and genetics. Finding genetic influence will not denigrate the role of education but will suggest new ways of thinking about effective education, such as recognizing that children create their own experience within the educational process in part on the basis of their genetic propensities.

DESCRIPTION (provided by applicant): Reading disability is by far the most frequently diagnosed form of childhood learning disability, affecting between 5 and 10% of school-age children. Although several genome-wide linkage studies have been reported for reading disability, more powerful association studies have been limited to fine mapping of linkage regions and to small numbers of candidate genes. The proposed genetic research will use an innovative strategy to detect some of the associations between reading disability and quantitative trait loci (QTLs) of small effect size: using single-nucleotide polymorphism (SA/P) microarrays and pooled DNA (SNP-MaP). Pooled DNA makes it possible to study very large samples in order to provide statistical power to detect QTLs of small effect size. The Affymetrix GeneChip[unreadable] Human Mapping 500K Array Set will genotype more than 500,000 SNPs. SNP-MaP using the 500K microarray set is a powerful tool for screening the genome systematically, efficiently, and inexpensively. SNPs nominated by this screening tool will be individually genotyped to confirm their association with reading disability. DNA and reading data already obtained for 5000 pairs of 7-year-old twins will be used in two independent studies to screen the 500K GeneChip using pooled DNA: low versus high MZ twins and low versus high DZ twins. Each of these 4 groups will have an N of about 500 and will be divided into 5 subpools of about 100 in order to estimate sampling variance. The 20 subpools will be genotyped twice on 500K GeneChips. This design will provide 99% power to detect a QTL that accounts for 1% of the variance (p = .001). From the results of these two studies, the 150 most significant SNPs will be selected for individual genotyping. 8200 children (one member of 1800 MZ pairs; both members of 3200 DZ pairs) will be individually genotyped in order to confirm the results of the two DNA pooling studies using variance components analysis but also testing the QTL hypothesis that the SNP associations operate across the population. The composite SNP-set will be useful as a genetic risk index in behavioral genomic research on reading. Finding replicated QTL associations responsible for the high heritability of reading will facilitate research on causal pathways between genes, brain and reading disability. Identifying genes associated with reading disability will eventually lead to better diagnoses, individually tailored treatments, and interventions that can prevent the development of reading disability.

DESCRIPTION (provided by applicant): Translational stress research has aimed to elucidate the biological mechanisms through which psychological stress influences disease pathophysiology in humans. Advancement in this field has been challenged by a technology gap that forces researchers to employ either comprehensive but invasive methods (e.g., genomic profiling after venipuncture) or minimally-invasive but non-comprehensive methods (e.g., salivary assays). AIM. We aim to validate a comprehensive and minimally-invasive method to study stress biology in humans, by testing whether minimally-invasive blood collection methods, namely dried blood spots and capillary blood collection, could be used to detect stress-related changes in genome-wide expression patterns. METHODS. First, for laboratory validation, we will collect RNA from dried blood spots, capillary blood, and venous blood in 10 healthy volunteers. We will then test the reliability, the validity, and the sensitivity of genomic profiles from minimally-invasive specimen-collection procedures. These tests will inform the choice of dried blood spots or capillary blood for specimen collection in a clinical validation. Second, for clinical validation, we will ask a population-representative sample of 1,250 pairs of 16-year-old UK monozygotic twins followed-up by the Twins Early Development Study (TEDS) to complete a computerized version of the Perceived Stress Scale and we will select the 35 most discordant twin pairs on this measure. We will then test whether microarray analysis from minimally-invasive assays can identify gene expression differences in pairs of young individuals with identical DNA sequences but different exposure to stress. IMPLICATIONS. The validation of a minimally-invasive assay to study the genomic fingerprint of stress will provide researchers with the technology needed to perform comprehensive assessment of stress biology in larger, more population-representative, and younger human samples. PUBLIC HEALTH RELEVANCE: A critical barrier to the advancement of translational stress research is the lack of minimally-invasive and comprehensive methods to assess stress-related biological changes in humans. We propose to carry out the validation of a safe, simple and comparatively painless procedure to study stress-related changes in genome-wide expression patterns. This project will provide researchers with the technology needed to perform comprehensive assessment of stress biology in larger, younger and more population-representative human samples.

DESCRIPTION (provided by applicant): Translational stress research has aimed to elucidate the biological mechanisms through which psychological stress influences disease pathophysiology in humans. Advancement in this field has been challenged by a technology gap that forces researchers to employ either comprehensive but invasive methods (e.g., genomic profiling after venipuncture) or minimally-invasive but non-comprehensive methods (e.g., salivary assays). AIM. We aim to validate a comprehensive and minimally-invasive method to study stress biology in humans, by testing whether minimally-invasive blood collection methods, namely dried blood spots and capillary blood collection, could be used to detect stress-related changes in genome-wide expression patterns. METHODS. First, for laboratory validation, we will collect RNA from dried blood spots, capillary blood, and venous blood in 10 healthy volunteers. We will then test the reliability, the validity, and the sensitivity of genomic profiles from minimally-invasive specimen-collection procedures. These tests will inform the choice of dried blood spots or capillary blood for specimen collection in a clinical validation. Second, for clinical validation, we will ask a population-representative sample of 1,250 pairs of 16-year-old UK monozygotic twins followed-up by the Twins Early Development Study (TEDS) to complete a computerized version of the Perceived Stress Scale and we will select the 35 most discordant twin pairs on this measure. We will then test whether microarray analysis from minimally-invasive assays can identify gene expression differences in pairs of young individuals with identical DNA sequences but different exposure to stress. IMPLICATIONS. The validation of a minimally-invasive assay to study the genomic fingerprint of stress will provide researchers with the technology needed to perform comprehensive assessment of stress biology in larger, more population-representative, and younger human samples.