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Biomedical subjects

John C DeFries

Publications and source records attributed to John C DeFries.

At least 19 recordsLinked to original sources
PubMed2006

Genetic influences on reading difficulties in boys and girls: the Colorado twin study.

To test the hypothesis that the genetic etiology for reading disability may differ in males and females, data from identical and fraternal twin pairs were analysed using both concordance and multiple regression methods. The sample included 264 identical (129 male, 135 female) and 214 same-sex fraternal (121 male, 93 female) twin pairs in which at least one member of each pair had reading difficulties. The difference between the identical and fraternal twin pair concordance rates was slightly larger for females than for males, suggesting a possible sex difference in etiology; however, a loglinear analysis of the three-way interaction of sex, zygosity, and concordance was not significant (p> or = 0.17). The estimate of group heritability (h2g), a standardized measure of the extent to which reading difficulties are due to genetic influences, was somewhat greater for females than males (0.65 vs 0.54), but this difference was also not significant (p > or = 0.35). Gender differences in h2g were larger for younger children (less than 11.5 years of age) than for older children. However, the three-way interaction of sex, zygosity, and age was not significant when age was treated either categorically (p > or = 0.86) or continuously (p > or = 0.71). Thus, results of this study provide little or no evidence for a differential genetic etiology of reading difficulties in males and females.

Catchment Area, Health↗
PubMed2006

Processing speed deficits in attention deficit/hyperactivity disorder and reading disability.

The goal of the current study was to test whether deficits in processing speed (PS) may be a shared cognitive risk factor in reading disability (RD) and Attention Deficit/Hyperactivity Disorder (ADHD), which are known to be comorbid. Literature on ADHD and RD suggests that deficits on tasks with a speeded component are seen in both of these disorders individually. The current study examined a wide range of speeded tasks in RD, ADHD, comorbid RD+ADHD, and a control group to test whether RD and ADHD have similar profiles of PS deficits, and whether these deficits are shared by the two disorders. The results suggest that a general PS deficit exists in both clinical groups compared to controls, although children with RD demonstrate greater PS deficits than children with ADHD. Two tests (underadditivity and partial correlations) were conducted to test whether these PS deficits are shared. Since we found that PS deficits were underadditive in the comorbid group and that partialling PS reduced the correlation between RD and ADHD, it appears that PS is a shared cognitive risk factor that may help explain the comorbidity of these two disorders.

Adolescent↗
PubMed2005

DCDC2 is associated with reading disability and modulates neuronal development in the brain.

DYX2 on 6p22 is the most replicated reading disability (RD) locus. By saturating a previously identified peak of association with single nucleotide polymorphism markers, we identified a large polymorphic deletion that encodes tandem repeats of putative brain-related transcription factor binding sites in intron 2 of DCDC2. Alleles of this compound repeat are in significant disequilibrium with multiple reading traits. RT-PCR data show that DCDC2 localizes to the regions of the brain where fluent reading occurs, and RNA interference studies show that down-regulation alters neuronal migration. The statistical and functional studies are complementary and are consistent with the latest clinical imaging data for RD. Thus, we propose that DCDC2 is a candidate gene for RD.

Adult↗
PubMed2005

TDT-association analysis of EKN1 and dyslexia in a Colorado twin cohort.

A candidate gene, EKN1, was recently described in a cohort from Finland for the dyslexia locus on chromosome 15q, DYX1. This report described a (2;15) (q11;21) translocation disrupting EKN1 that cosegregated with dyslexia in a two-generation family. It also characterized a sequence polymorphism in the 5' untranslated region and a missense mutation that showed significant association in 109 dyslexics compared to 195 controls (p=0.002 and p=0.006, respectively). To confirm these results we interrogated the same polymorphisms in a cohort of 150 nuclear families with dyslexia ascertained through the Colorado Learning Disabilities Research Center. Using QTDT analysis with nine individual quantitative tasks and two composite measures of reading performance, we could not replicate the reported association. We conclude that the polymorphisms identified in the Finland sample are unlikely to be functional DNA changes contributing to dyslexia, and that if variation in EKN1 is causal such changes are more likely to be in regulatory regions that were not sequenced in this study. Alternatively, the published findings of association with markers in EKN1 may reflect linkage disequilibrium with variation in another gene(s) in the region.

Base Sequence↗
PubMed2005

Genetic etiology of reading difficulties in boys and girls.

Although it has been suggested that genetic influences on reading difficulties may differ in boys and girls, results obtained from previous analyses of data from same-sex twin pairs have failed to provide evidence for a differential genetic etiology of reading disability (RD) as a function of gender. However, results of a recent study in which data from both same-sex and opposite-sex twin pairs were analyzed indicated a higher heritability for reading difficulties in boys (Harlaar et al., 2005). Because the current sample of twin pairs tested in the Colorado Learning Disabilities Research Center is substantially larger than that analyzed for our previous report (Wadsworth et al., 2000), this hypothesis was tested more rigorously using data from both same-sex and opposite-sex twin pairs in our current augmented sample. Composite reading scores from 634 twin pairs were subjected to DeFries-Fulker sex-limitation analysis using the model-fitting approach of Purcell and Sham (2003). Analysis of data from the combined sample of male and female twins indicated that genetic influences account for more than half the proband reading deficit (h2g = .58). When this model was extended to test for gender differences in the magnitude of genetic influences on RD, h2g estimates were somewhat higher for females than for males (.63 and .53, respectively), but the difference was nonsignificant (p > .3). A test for qualitative gender differences was also nonsignificant. Thus, these results provide little evidence for a differential genetic etiology of RD in boys and girls.

Adolescent↗
PubMed2004

A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States.

Several quantitative trait loci (QTLs) that influence developmental dyslexia (reading disability [RD]) have been mapped to chromosome regions by linkage analysis. The most consistently replicated area of linkage is on chromosome 6p23-21.3. We used association analysis in 223 siblings from the United Kingdom to identify an underlying QTL on 6p22.2. Our association study implicates a 77-kb region spanning the gene TTRAP and the first four exons of the neighboring uncharacterized gene KIAA0319. The region of association is also directly upstream of a third gene, THEM2. We found evidence of these associations in a second sample of siblings from the United Kingdom, as well as in an independent sample of twin-based sibships from Colorado. One main RD risk haplotype that has a frequency of approximately 12% was found in both the U.K. and U.S. samples. The haplotype is not distinguished by any protein-coding polymorphisms, and, therefore, the functional variation may relate to gene expression. The QTL influences a broad range of reading-related cognitive abilities but has no significant impact on general cognitive performance in these samples. In addition, the QTL effect may be largely limited to the severe range of reading disability.

Chromosome Mapping↗
PubMed2004

Refinement of the 6p21.3 quantitative trait locus influencing dyslexia: linkage and association analyses.

Reading disability (RD), or dyslexia, is the most common learning disability with a prevalence rate of ~5%-10% in school-age children. RD is highly heritable with evidence of a neurobiological origin. Linkage studies have identified several quantitative trait loci (QTLs) for RD. The QTL on chromosome 6p21.3 has been independently replicated by several groups and spans a 16.4-Mb (13.8 cM) interval from D6S109 to D6S291. In this study, we performed sib-pair linkage analyses with Haseman-Elston and DeFries-Fulker methods to define more accurately the QTL interval. Linkage was assessed by using five quantitative phenotypes, including a composite measure of reading performance and four component phenotypes. When probands were selected for severe scores, single- and multi-point analyses showed significant linkage with all five phenotypes, converging over an interval of ~3.24 Mb spanning D6S1597 to D6S1571. Maximal linkage converged at marker D6S1554 across phenotypes. Out of 12 genes in the linkage interval, ten clustered within ~680 kb and were selected for association analysis based on central nervous system expression and putative function. Marker-trait associations were assessed by using QTDT (a general test of association for quantitative traits) and the family-based association test (FBAT), and haplotype analysis was performed by using FBAT and the GeneHunter Transmission/Disequilibrium Test TDT. Marker associations were detected in five of the ten genes, results that were corroborated by our haplotype TDT analysis. The results of the association study have thereby allowed us to significantly reduce the number of possible candidate genes and to prioritize genes for further mutation screening.

Adolescent↗
PubMed2004

Multivariate analysis of quantitative trait loci influencing variation in anxiety-related behavior in laboratory mice.

The number and mode of action of quantitative trait loci (QTL) that contribute to behavioral variation in rodents is still largely unknown. On theoretical grounds, multivariate techniques are expected to yield new insights into this problem, but there are only a few examples of its application in practice. Here we explore the power of multivariate approaches to uncover the genetic architecture of 23 anxiety-related phenotypes in 1636 F2 laboratory mice. We detected QTL with a genome-wide significance threshold of P < 0.05 on 14 chromosomes, of which 10 correspond to those identified by univariate analysis. Novel QTL were found on Chromosomes 3, 9, 13, and 17. Thus, multivariate analyses increased the yield of QTL exceeding a genome-wide significance threshold by 40%. On the basis of these results and by the application of a QTL estimator, we show that the mean number of QTL influencing anxiety-related behavior in mice is 6, with a 95% upper limit of 14.

Animals↗
PubMed2004

Little epistasis for anxiety-related measures in the DeFries strains of laboratory mice.

Recent advances in methodologies for testing epistatic interactions, combined with several successes in demonstrating genetic interaction effects in animal and human genetics, have rekindled interest in the role of epistatic influences on complex traits. It has even been suggested that the unacknowledged presence of epistasis vitiates the genetic dissection of human and animal behavior. Here we report a genome-wide interaction analysis of 1636 F2 mice to show that epistasis is of minimal importance in an animal model of anxiety. By using a sufficiently large sample of F2 animals, we provide evidence that interaction effects between any two loci contribute less than 5% to the total phenotypic variance in multiple tests of anxiety. We conclude that interactions between loci do not necessarily vitiate the genetic analysis of behavior in at least one animal model of anxiety.

Analysis of Variance↗
PubMed2004

Genetic structure of the LXS panel of recombinant inbred mouse strains: a powerful resource for complex trait analysis.

The set of LXS recombinant inbred (RI) strains is a new and exceptionally large mapping panel that is suitable for the analysis of complex traits with comparatively high power. This panel consists of 77 strains-more than twice the size of other RI sets--and will typically provide sufficient statistical power (beta = 0.8) to map quantitative trait loci (QTLs) that account for approximately 25% of genetic variance with a genomewide p < 0.05. To characterize the genetic architecture of this new set of RI strains, we genotyped 330 MIT microsatellite markers distributed on all autosomes and the X Chromosome and assembled error-checked meiotic recombination maps that have an average F2-adjusted marker spacing of approximately 4 cM. The LXS panel has a genetic structure consistent with random segregation and subsequent fixation of alleles, the expected 3-4 x map expansion, a low level of nonsyntenic association among loci, and complete independence among all 77 strains. Although the parental inbred strains-Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS)--were derived originally by selection from an 8-way heterogeneous stock selected for differential sensitivity to sedative effects of ethanol, the LXS panel is also segregating for many other traits. Thus, the LXS panel provides a powerful new resource for mapping complex traits across many systems and disciplines and should prove to be of great utility in modeling the genetics of complex diseases in human populations.

Alleles↗
PubMed2004

QTL analysis of multiple behavioral measures of anxiety in mice.

In a test battery consisting of an open-field arena, a light-dark box, a mirror-chamber box, an elevated plus maze, and an elevated square maze, 1,671 mice were tested, generating over 100 putative measures of anxiety in rodents. Quantitative trait loci (QTL) analysis was carried out on all measures, plus composite measures and phenotypic factor scores. Significant LOD scores were found for QTL on 17 chromosomes, with large and consistent QTL behavioral effects on chromosomes 1, 4, 7, 8, 14, 15, l8, and X. QTL on chromosomes 4 and 8 largely influence locomotor activity in both home cages and novel environments, whereas QTL on chromosomes 1, 15, and 18 influence anxiety-related behaviors. Five genetically separable, cross-test dimensions of anxiety could be identified: (i) the suppression of locomotor activity in low to moderately anxiogenic regions of the tests; (ii) a shift toward proportionally less time and activity spent in high-anxiogenic test areas; (iii) the suppression of rearing behavior; (iv) increased latency to enter novel areas; (v) increased autonomic responses, as assessed by defecation and urination. Patterns of QTL influence on cross-test composite scores were distinctive. For example, the QTL on chromosome 1 strongly influenced safe-area locomotor activity (LOD = 35) and autonomic responses (LOD = 16), whereas the QTL on chromosome 15 influenced the proportion of activity in high-anxiogenic areas (LOD = 16), latency to enter novel areas (LOD = 36) and rearing behavior (LOD = 57). Phenotypic factor analysis identified factors heavily loaded on single tests, rather than cross-test factors. The use of factor analysis or within-test principal components for data reduction before genetic analysis was less satisfactory than using genetic dissection methods on the original measures and logically derived composites.

Animals↗
PubMed2004

Genetic and environmental contributions to general cognitive ability through the first 16 years of life.

The genetic and environmental contributions to the development of general cognitive ability throughout the first 16 years of life were examined using sibling data from the Colorado Adoption Project. Correlations were analyzed along with structural equation models to characterize the genetic and environmental influences on longitudinal stability and instability. Intraclass correlations reflected both considerable genetic influence at each age and modest shared environmental influence within and across ages. Modeling results suggested that genetic factors mediated phenotypic stability throughout this entire period, whereas most age-to-age instability appeared to be due to nonshared environmental influences.

Adolescent↗
PubMed2004

Causal models of reading disability: a twin study.

The genetic and environmental relationships among measures of phoneme awareness, naming speed, Intelligence Quotient (IQ), and reading performance were investigated in 623 identical and fraternal twin pairs tested in the Colorado Learning Disabilities Research Center. A Cholesky decomposition analysis of these measures provided evidence supporting the double deficit hypothesis that difficulties in phonological processing and naming speed both contribute to reading disability. Additionally, the model revealed marginally significant genetic and significant non-shared environmental relationships between IQ and reading independent of naming speed and phoneme awareness. Thus a more complete causal model of reading disability should include IQ as well as measures of phonological processing and naming speed.

Dyslexia↗
PubMed2002

Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attention-deficit/hyperactivity disorder.

Comorbidity is pervasive among both adult and child psychiatric disorders; however, the etiological mechanisms underlying the majority of comorbidities are unknown. This study used genetic linkage analysis to assess the etiology of comorbidity between reading disability (RD) and attention-deficit hyperactivity disorder (ADHD), two common childhood disorders that frequently co-occur. Sibling pairs (N = 85) were ascertained initially because at least one individual in each pair exhibited a history of reading difficulties. Univariate linkage analyses in sibling pairs selected for ADHD from within this RD-ascertained sample suggested that a quantitative trait locus (QTL) on chromosome 6p is a susceptibility locus for ADHD. Because this QTL is in the same region as a well-replicated QTL for reading disability, subsequent bivariate analyses were conducted to test if this QTL contributed to comorbidity between the two disorders. Analyses of data from sib pairs selected for reading deficits revealed suggestive bivariate linkage for ADHD and three measures of reading difficulty, indicating that comorbidity between RD and ADHD may be due at least in part to pleiotropic effects of a QTL on chromosome 6p.

Analysis of Variance↗
PubMed2002

Dopamine transporter polymorphism associated with externalizing behavior problems in children.

Early childhood externalizing behavior is a stable and heritable pattern of aggressive and delinquent behavior that often leads to the development of serious psychiatric disorders such as conduct disorder and attention deficit hyperactivity disorder. We examined the relationship between parent reported externalizing behavior (assessed at ages 4, 7, and 9 years) and the VNTR polymorphism of the 3' untranslated region of SLC6A3 (DAT1) in a community sample of 790 children ascertained as part of our longitudinal twin and adoption studies. We applied the sibling-based methodology developed by Fulker et al. [1999: Am J Hum Genet 64:259-267] for estimating allelic association with quantitative traits, while controlling for population stratification. An extension of these methods allowed for the inclusion of monozygotic twins, dizygotic twins, siblings, and singletons. We have demonstrated that the 9-repeat variant of the DAT1 is a significant risk allele for externalizing behavior at ages 4 (P=0.001) and 7 years (P=0.02). Although the effect size was negligible at age 9 (P=0.92), a formal test of the developmental decrease in effect across the three ages was non-significant (P=0.70).

Adolescent↗
PubMed2002

Differential genetic etiology of reading component processes as a function of IQ.

Results obtained from previous studies of word recognition, reading component skills, and reading composite measures suggest that genetic factors may be more important as a cause for reading disability among children with higher IQ scores than among those with lower IQ scores. To investigate the genetic etiology of reading disability further, measures of word recognition, phonological decoding, orthographic coding, and phoneme awareness were obtained from a total of 465 twin pairs with a positive school history of reading problems. The basic and extended DeFries and Fulker (DF) multiple regression models for the analysis of selected twin data were employed to investigate the etiology of group deficits in reading and language skills, as well as to assess differential genetic etiology for the reading-related measures as a function of IQ. Data from 168 sibling pairs (drawn from the twins' families), including fraternal twin pairs and their siblings, as well as non-twin siblings of identical twins were subjected to single-marker analyses using the DF basic linkage model to examine evidence for linkage of a quantitative-trait locus (QTL) for reading and language deficits to the short arm of chromosome 6. Lastly, to investigate the possible differential influence of this QTL as a function of IQ, the sibling pair data were fitted to an extension of the DF basic linkage model. Results indicated that reading and language deficits are significantly heritable and that differential genetic influences as a function of IQ are evident for measures of word recognition and phonological decoding. Results obtained from linkage analyses confirmed the presence of a QTL on chromosome 6p that influences phonological and orthographic skills, as well as phoneme awareness measures, and suggest that this QTL may influence phoneme awareness differentially as a function of IQ: however, future analyses with considerably larger samples are needed to test the hypothesis of differential QTL influence more rigorously.

Adolescent↗
PubMed2002

Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus: quantitative association analysis and positional candidate genes SEMA4F and OTX1.

A locus on chromosome 2p12-16 has been implicated in dyslexia susceptibility by two independent linkage studies, including our own study of 119 nuclear twin-based families, each with at least one reading-disabled child. Nonetheless, no variant of any gene has been reported to show association with dyslexia, and no consistent clinical evidence exists to identify candidate genes with any strong a priori logic. We used 21 microsatellite markers spanning 2p12-16 to refine our 1-LOD unit linkage support interval to 12cM between D2S337 and D2S286. Then, in quantitative association analysis, two microsatellites yielded P values<0.05 across a range of reading-related measures (D2S2378 and D2S2114). The exon/intron borders of two positional candidate genes within the region were characterized, and the exons were screened for polymorphisms. The genes were Semaphorin4F (SEMA4F), which encodes a protein involved in axonal growth cone guidance, and OTX1, encoding a homeodomain transcription factor involved in forebrain development. Two non-synonymous single nucleotide polymorphisms were found in SEMA4F, each with a heterozygosity of 0.03. One intronic single nucleotide polymorphism between exons 12 and 13 of SEMA4F was tested for quantitative association, but no significant association was found. Only one single nucleotide polymorphism was found in OTX1, which was exonic but silent. Our data therefore suggest that linkage with reading disability at 2p12-16 is not caused by coding variants of SEMA4F or OTX1. Our study outlines the approach necessary for the identification of genetic variants causing dyslexia susceptibility in an epidemiological population of dyslexics.

Chromosome Mapping↗