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Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia., (© 2022. The Author(s).)

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10 -6 ) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at p T  = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10 -13 ), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10 -43 ), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10 -22 ), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10 -12 ), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10 -4 ), educational attainment (0.86[0.82; 0.91]; p = 2 × 10 -7 ), and intelligence (0.72[0.68; 0.76]; p = 9 × 10 -29 ). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence., (© 2020. The Author(s).)

Background: Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms., Objective: To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach., Methods: We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African-American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted., Results: Genome-wide significant effects were observed at rs1555839 (p=4.03×10 -8 ) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer-promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule., Conclusion: This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene-brain-behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Current definitions of specific learning disability (SLD) identify a heterogeneous population that includes individuals with weaknesses in reading, math, or writing, and these academic difficulties often co-occur in many of the same individuals. The Colorado Learning Disabilities Research Center (CLDRC) is an interdisciplinary, multisite research program that uses converging levels of analysis to understand the genetic and environmental etiology, neuropsychology, and developmental outcomes of SLDs in reading (RD), math (MD), and writing (WD), along with the comorbidity between these SLDs and other developmental disorders. The latest results from the CLDRC twin study suggest that shared genetic influences contribute to the significant covariance between all aspects of reading (word reading, reading fluency, and reading comprehension) and math (calculations, math fluency, and word problems), and distinct genetic or environmental influences also contribute to weaknesses in each specific academic domain. RD and MD are associated with a range of negative outcomes on both concurrent measures and measures of functional outcomes completed 5 years after the twins were first assessed. Over the next several years the CLDRC will continue to expand on this work by administering a comprehensive test battery that includes measures of all dimensions of academic achievement that are described in current definitions of SLD and incorporating these measures in new neuroimaging and molecular genetic studies., (© 2019 Wiley Periodicals, Inc.)

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10 -8 ) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10 -9 ), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10 -8 ). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10 -8 ) and with all the cognitive traits tested (p = 3.07 × 10 -8 ), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10 -5 -10 -7 ]) and negatively associated with ADHD PRS (p ~ [10 -8 -10 -17 ]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

Eleven loci with prior evidence for association with reading and language phenotypes were sequenced in 96 unrelated subjects with significant impairment in reading performance drawn from the Colorado Learning Disability Research Center collection. Out of 148 total individual missense variants identified, the chromosome 7 genes CCDC136 and FLNC contained 19. In addition, a region corresponding to the well-known DYX2 locus for RD contained 74 missense variants. Both allele sets were filtered for a minor allele frequency ≤0.01 and high Polyphen-2 scores. To determine if observations of these alleles are occurring more frequently in our cases than expected by chance in aggregate, counts from our sample were compared to the number of observations in the European subset of the 1000 Genomes Project using Fisher's exact test. Significant P values were achieved for both CCDC136/FLNC (P = 0.0098) and the DYX2 locus (P = 0.012). Taken together, this evidence further supports the influence of these regions on reading performance. These results also support the influence of rare variants in reading disability.

Background: Males are diagnosed with dyslexia more frequently than females, even in epidemiological samples. This may be explained by greater variance in males' reading performance., Methods: We expand on previous research by rigorously testing the variance difference theory, and testing for mediation of the sex difference by cognitive correlates. We developed an analytic framework that can be applied to group differences in any psychiatric disorder., Results: Males' overrepresentation in the low performance tail of the reading distribution was accounted for by mean and variance differences across sex. There was no sex difference at the high performance tail. Processing speed (PS) and inhibitory control partially mediated the sex difference. Verbal reasoning emerged as a strength in males., Conclusions: Our results complement a previous finding that PS partially mediates the sex difference in symptoms of attention deficit/hyperactivity disorder (ADHD), and helps explain the sex difference in both dyslexia and ADHD and their comorbidity., (© 2017 Association for Child and Adolescent Mental Health.)

Because of recent concerns about the replication of published results in the behavioral and biomedical sciences (Ioannidis, PLoS Medicine, Vol. 2, 2005, p. e124; Open Science Collaboration, Science, Vol. 349, 2015, p. 943; Pashler & Wagenmakers, Perspectives on Psychological Science, Vol. 7, 2012, pp. 528-530), we have conducted a replication of our recently published analyses of longitudinal reading performance and attention deficit-hyperactivity disorder data from twin pairs selected for reading difficulties (Wadsworth et al., Twin Research and Human Genetics, Vol. 18, 2015, pp. 755-761). Results obtained from univariate and bivariate (DeFries & Fulker, Behavior Genetics, Vol. 15, 1985, pp. 467-473; Acta Geneticae Medicae et Gemellologiae: Twin Research, Vol. 37, 1988, pp. 205-216) analyses of data from a subset of twin pairs tested in the International Longitudinal Twin Study of Early Reading Development at post-4th grade, and its continuation into high school at post-9th grade, were compared to those from our previous report. Similar measures of reading performance, the same measures of inattention and hyperactivity/impulsivity, and similar selection criteria were used in the two studies. In general, the patterns of results obtained from these two independent studies were highly similar. Thus, these results clearly illustrate the principle that findings from studies in quantitative behavioral genetics often replicate (Plomin et al., Perspectives on Psychological Science, Vol. 11, 2016, pp. 3-23).

Approximately 60% of children with reading difficulties (RD) meet criteria for at least one co-occurring disorder. The most common of these, attention deficit-hyperactivity disorder (ADHD), occurs in 20-40% of individuals with RD. Recent studies have suggested that genetic influences are responsible. To assess the genetic etiologies of RD and the comorbidity of RD and two ADHD symptom dimensions -- inattention (IN) and hyperactivity/impulsivity (H/I) -- we are conducting the first longitudinal twin study of RD and ADHD. Data from twin pairs in which at least one member of the pair met criteria for proband status for RD at initial assessment, and were reassessed 5 years later, were subjected to DeFries-Fulker (DF) analysis. Analyses of reading composite data indicated that over 60% of the proband deficit at initial assessment was due to genetic influences, and that reading deficits at follow-up were due substantially to the same genetic influences. When a bivariate DF model was fitted to reading performance and IN data, genetic influences accounted for 60% of contemporaneous comorbidity and over 60% of the longitudinal relationship. In contrast, analysis of the comorbidity between reading performance and H/I indicated that common genetic influences accounted for only about 20% of the contemporaneous and about 10% of the longitudinal relationships. Results indicate that (1) genetic influences on RD are substantial and highly stable; (2) the comorbidity between RD and IN is due largely to genetic influences, both contemporaneously and longitudinally; and (3) genetic influences contribute significantly less to the comorbidity between RD and H/I.

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome-wide association scan (GWAS) meta-analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading- and language-related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10(-7) for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on-going international efforts to identify genes contributing to reading and language skills., (© 2014 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Reading disability (RD) and language impairment (LI) are common neurodevelopmental disorders with moderately strong genetic components and lifelong implications. RD and LI are marked by unexpected difficulty acquiring and processing written and verbal language, respectively, despite adequate opportunity and instruction. RD and LI-and their associated deficits-are complex, multifactorial, and often comorbid. Genetic studies have repeatedly implicated the DYX2 locus, specifically the genes DCDC2 and KIAA0319, in RD, with recent studies suggesting they also influence LI, verbal language, and cognition. Here, we characterize the relationship of the DYX2 locus with RD, LI, and IQ. To accomplish this, we developed a marker panel densely covering the 1.4 Mb DYX2 locus and assessed association with reading, language, and IQ measures in subjects from the Avon Longitudinal Study of Parents and Children. We then replicated associations in three independent, disorder-selected cohorts. As expected, there were associations with known RD risk genes KIAA0319 and DCDC2. In addition, we implicated markers in or near other DYX2 genes, including TDP2, ACOT13, C6orf62, FAM65B, and CMAHP. However, the LD structure of the locus suggests that associations within TDP2, ACOT13, and C6orf62 are capturing a previously reported risk variant in KIAA0319. Our results further substantiate the candidacy of KIAA0319 and DCDC2 as major effector genes in DYX2, while proposing FAM65B and CMAHP as new DYX2 candidate genes. Association of DYX2 with multiple neurobehavioral traits suggests risk variants have functional consequences affecting multiple neurological processes. Future studies should dissect these functional, possibly interactive relationships of DYX2 candidate genes.

Reading disability (RD) and math disability (MD) frequently co-occur, but the etiology of this comorbidity is not well understood. Groups with RD only (N = 241), MD only (N = 183), and RD + MD (N = 188) and a control group with neither disorder (N = 411) completed a battery of measures of internalizing and externalizing psychopathology, social and academic functioning, and 10 neuropsychological processes. Groups with RD only, MD only, and RD + MD were significantly impaired versus the control group on nearly all measures, and the group with RD + MD was more impaired than the groups with MD and RD alone on measures of internalizing psychopathology, academic functioning, and 7 of 10 neuropsychological constructs. Multiple regression analyses of the neuropsychological measures indicated that deficits in reading and math were associated with shared weaknesses in working memory, processing speed, and verbal comprehension. In contrast, reading difficulties were uniquely associated with weaknesses in phoneme awareness and naming speed, and math deficits were uniquely associated with weaknesses in set shifting. These results support multiple-deficit neuropsychological models of RD and MD and suggest that RD and MD are distinct but related disorders that co-occur because of shared neuropsychological weaknesses in working memory, processing speed, and verbal comprehension.

Reading difficulties are both heritable and stable; however, little is known about the etiology of this stability. Results from a preliminary analysis of data from 56 twin pairs who participated in the Colorado Longitudinal Twin Study of Reading Disability (Astrom et al., Twin Res Hum Genet 10:434-439, 2007) suggested that about two-thirds of the proband deficit at follow-up was due to genetic factors that also influenced deficits at their initial assessment. Although our proband sample is now nearly twice as large, it is still relatively small; thus, to increase power, we subjected data from probands, co-twins and their nontwin siblings to a novel extension of DeFries-Fulker analysis (DeFries and Fulker, Behav Genet 15:467-473, 1985; DeFries and Fulker, Acta Genet Med Gemellol, 37, 205-216, 1988). In addition to providing estimates of univariate and bivariate heritability, this analysis facilitates a test of the difference between shared environmental influences for twins versus siblings. Longitudinal composite reading performance scores at 10.6 and 15.5 years of age, on average, were analyzed from 33 MZ and 64 DZ twin pairs in which at least one member of each pair had reading difficulties, and from 44 siblings of the probands. Scores were highly stable (.86 ± .03, across probands, co-twins and siblings) and heritability of the group deficit at initial assessment was .67 ± .22. Longitudinal bivariate heritability was .59 ± .21, suggesting that nearly 60% of the proband reading deficit at follow-up is due to genetic factors that influenced reading difficulties at the initial assessment. However, tests for special twin environmental influences were nonsignificant.

In order to test the hypothesis that the genetic etiology of reading disability differs as a function of IQ, composite reading performance data from 308 pairs of identical (monozygotic, MZ) twins and 440 pairs of fraternal (dizygotic, DZ) twins (254 same-sex and 186 opposite-sex) in which at least one member of each pair was classified as reading-disabled were subjected to multiple regression analysis (DeFries and Fulker, Behav Genet 15:467-473, 1985; Acta Genet Med Gemellol 37:205-216, 1988). In the total sample, heritability of the group deficit in reading performance (h(g)(2)) was .61 (±.06). However, results of fitting an extended regression model to reading performance and IQ data suggested that the genetic etiology of reading disability differs as a linear function of IQ (p ≤ .04). When the basic regression model was fitted separately to data from twin pairs with Wechsler (Examiner's manual: Wechsler intelligence scale for children-revised, 1974; Examiner's manual: Wechsler adult intelligence scale-revised, 1981) Full Scale IQ scores in the upper and lower 25% of the sample, resulting estimates of h(g)(2) were .75 (±.12) and .50 (±.10), respectively (p ≤ .045). These results suggest that reading difficulties in children with a higher IQ are due substantially to genetic influences and may require intensive remediation efforts.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are complex childhood disorders that frequently co-occur, but the etiology of this comorbidity remains unknown., Method: Participants were 457 twin pairs from the Colorado Learning Disabilities Research Center (CLDRC) twin study, an ongoing study of the etiology of RD, ADHD, and related disorders. Phenotypic analyses compared groups with and without RD and ADHD on composite measures of six cognitive domains. Twin analyses were then used to test the etiology of the relations between the disorders and any cognitive weaknesses., Results: Phenotypic analyses supported the hypothesis that both RD and ADHD arise from multiple cognitive deficits rather than a single primary cognitive deficit. RD was associated independently with weaknesses on measures of phoneme awareness, verbal reasoning, and working memory, whereas ADHD was independently associated with a heritable weakness in inhibitory control. RD and ADHD share a common cognitive deficit in processing speed, and twin analyses indicated that this shared weakness is primarily due to common genetic influences that increase susceptibility to both disorders., Conclusions: Individual differences in processing speed are influenced by genes that also increase risk for RD, ADHD, and their comorbidity. These results suggest that processing speed measures may be useful for future molecular genetic studies of the etiology of comorbidity between RD and ADHD., (Copyright © 2010 Elsevier Srl. All rights reserved.)

Background: Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis., Methodology/principal Findings: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L)., Conclusions: Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.

The prevalence of reading difficulties is typically higher in males than females in both referred and research-identified samples, and the ratio of males to females is greater in more affected samples. To explore possible gender differences in reading performance, we analysed data from 1133 twin pairs in which at least one member of each pair had a school history of reading problems and from 684 twin pairs from a comparison sample with no reading difficulties. Although the difference between the average scores of males and females in these two samples was very small, the variance of reading performance was significantly greater for males in both groups. We suggest that a greater variance of reading performance measures in males may account at least in part for their higher prevalence of reading difficulties as well as for the higher gender ratios that are observed in more severely impaired samples., ((c) 2009 John Wiley & Sons, Ltd.)

This article examines Gene x Environment (G x E) interactions in two comorbid developmental disorders--reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD)--as a window on broader issues on G x E interactions in developmental psychology. The authors first briefly review types of G x E interactions, methods for detecting them, and challenges researchers confront in interpreting such interactions. They then review previous evidence for G x E interactions in RD and ADHD, the directions of which are opposite to each other: bioecological for RD and diathesis stress for ADHD. Given these results, the authors formulate and test predictions about G x E interactions that would be expected at the favorable end of each symptom dimension (e.g., above-average reading or attention). Consistent with their prediction, the authors found initial evidence for a resilience interaction for above-average reading: higher heritability in the presence of lower parental education. However, they did not find a G x E interaction at the favorable end of the ADHD symptom dimension. The authors conclude with implications for future research.

Environmental moderation of the level of genetic influence on children's reading disabilities was explored in a sample of 545 identical and fraternal twins (mean age = 11.5 years). Parents' number of years of education, which is correlated with a broad range of environmental factors related to reading development, was significantly related to the level of genetic influence on reading disability. Genetic influence was higher and environmental influence was lower among children whose parents had a high level of education, compared with children whose parents had a lower level of education. We discuss the implications of these results for behavior genetic and molecular genetic research, for the diagnosis and remediation of reading disabilities, and for policy in public education.

The primary objectives of the present study are to introduce the Colorado Longitudinal Twin Study of Reading Disability, the first longitudinal twin study in which subjects have been specifically selected for having a history of reading difficulties, and to present some initial assessments of the stability of reading performance and cognitive abilities in this sample. Preliminary examination of the test scores of 124 twins with a history of reading difficulties and 154 twins with no history of reading difficulties indicates that over the 5- to 6-year interval between assessments, cognitive and reading performance are highly stable. As a group, those subjects with a history of reading difficulties had substantial deficits relative to control subjects on all measures at initial assessment, and significant deficits remained at follow-up. The stability noted for all cognitive and achievement measures was highest for a composite measure of reading, whose average stability correlation across groups was 0.80. Results of preliminary behavior genetic analyses for this measure indicated that shared genetic influences accounted for 86% and 49% of the phenotypic correlations between the two assessments for twin pairs with and without reading difficulties, respectively. In addition, genetic correlations reached unity for both groups, suggesting that the same genetic influences are manifested at both time points.

A community sample of twins in which at least one member of each pair exhibited significant reading difficulties (99 monozygotic and 80 dizygotic pairs) or symptoms of attention-deficit/hyperactivity disorder (ADHD; 83 monozygotic and 78 dizygotic pairs) was used to test the etiology of comorbidity between reading disability (RD) and ADHD. Univariate analyses revealed moderate to high heritability for all measures of reading difficulty and ADHD. Subsequent bivariate analyses indicated that the relation between reading difficulties and inattention symptoms is primarily attributable to common genetic influences, whereas bivariate heritability estimates were not significant for hyperactivity-impulsivity and any of the reading measures. Reading difficulties and ADHD symptoms were more highly heritable if the proband met criteria for both disorders versus RD or ADHD alone, suggesting that future molecular genetic analyses of comorbid RD + ADHD may facilitate the identification of susceptibility genes for RD, ADHD, and their comorbidity., (Copyright 2007 Wiley-Liss, Inc.)

Results obtained from previous longitudinal studies of reading difficulties indicate that reading deficits are generally stable. However, little is known about the etiology of this stability. Thus, the primary objective of this first longitudinal twin study of reading difficulties is to provide an initial assessment of genetic and environmental influences on the stability of reading deficits. Data were analyzed from a sample of 56 twin pairs, 18 identical (monozygotic, MZ) and 38 fraternal (dizygotic, DZ), in which at least one member of each pair was classified as reading-disabled in the Colorado Learning Disabilities Research Center, and on whom follow-up data were available. The twins were tested at two time points (average age of 10.3 years at initial assessment and 16.1 years at follow-up). A composite measure of reading performance (PIAT Reading Recognition, Reading Comprehension and Spelling) was highly stable, with a stability correlation of .84. Data from the initial time point were first subjected to univariate DeFries-Fulker multiple regression analysis and the resulting estimate of the heritability of the group deficit (h2g) was .84 (+/-.26). When the initial and follow-up data were then fitted to a bivariate extension of the basic DF model, bivariate heritability was estimated at .65, indicating that common genetic influences account for approximately 75% of the stability between reading measures at the two time points.

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.

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.

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.

Background: There is a growing interest in the study of the genetic origins of comorbidity, a direct consequence of the recent findings of genetic loci that are seemingly linked to more than one disorder. There are several potential causes for these shared regions of linkage, but one possibility is that these loci may harbor genes with manifold effects. The established genetic correlation between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD) suggests that their comorbidity is due at least in part to genes that have an impact on several phenotypes, a phenomenon known as pleiotropy., Methods: We employ a bivariate linkage test for selected samples that could help identify these pleiotropic loci. This linkage method was employed to carry out the first bivariate genome-wide analysis for RD and ADHD, in a selected sample of 182 sibling pairs., Results: We found evidence for a novel locus at chromosome 14q32 (multipoint LOD=2.5; singlepoint LOD=3.9) with a pleiotropic effect on RD and ADHD. Another locus at 13q32, which had been implicated in previous univariate scans of RD and ADHD, seems to have a pleiotropic effect on both disorders. 20q11 is also suggested as a pleiotropic locus. Other loci previously implicated in RD or ADHD did not exhibit bivariate linkage., Conclusions: Some loci are suggested as having pleiotropic effects on RD and ADHD, while others might have unique effects. These results highlight the utility of this bivariate linkage method to study pleiotropy.

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.

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.

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.

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.

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.

Reading disability (RD), or dyslexia, is a common heterogeneous syndrome with a large genetic component. Several studies have consistently found evidence for a quantitative-trait locus (QTL) within the 17 Mb (14.9 cM) that span D6S109 and D6S291 on chromosome 6p21.3-22. To characterize further linkage to the QTL, to define more accurately the location and the effect size, and to identify a peak of association, we performed Haseman-Elston and DeFries-Fulker linkage analyses, as well as transmission/disequilibrium, total-association, and variance-components analyses, on 11 quantitative reading and language phenotypes. One hundred four families with RD were genotyped with a new panel of 29 markers that spans 9 Mb of this region. Linkage results varied widely in degree of statistical significance for the different linkage tests, but multipoint analysis suggested a peak near D6S461. The average 6p QTL heritability for the 11 reading and language phenotypes was 0.27, with a maximum of 0.66 for orthographic choice. Consistent with the region of linkage described by these studies and others, there was a peak of transmission disequilibrium with a QTL centered at JA04 (chi2=9.48; empirical P=.0033; orthographic choice), and there was strong evidence for total association at this same marker (chi2=11.49; P=.0007; orthographic choice). Although the boundaries of the peak could not be precisely defined, the most likely location of the QTL is within a 4-Mb region surrounding JA04.

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., (Copyright 2002 Wiley-Liss, Inc.)

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.

Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem. It is well established that dyslexia is a significantly heritable trait with a neurobiological basis. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P< or =0.0004 for single word-reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait.

Children with reading deficits perform more slowly than normally-achieving readers on speed of processing measures, such as rapid naming (RN). Although rapid naming is a well-established correlate of reading performance and both are heritable, few studies have attempted to assess the cause of their covariation. Measures of rapid naming (numbers, colors, objects, and letters subtests), phonological decoding, orthographic choice, and a composite variable (DISCR) derived from the reading recognition, reading comprehension, and spelling subtests of the Peabody Individual Achievement Test were obtained from a total of 550 twin pairs with a positive school history of reading problems. Basic DeFries and Fulker (DF) multiple regression models for the analysis of selected twin data confirmed the heritable nature of phonological decoding, orthographic choice, DISCR, and rapid-naming composites. Bivariate DF models were employed to examine the extent to which deficits in the three reading-related measures covary genetically with rapid naming. Significant bivariate heritability estimates for each of the reading measures with the numbers and letters rapid-naming composite were also obtained. As expected, univariate sib-pair linkage analyses indicated the presence of a quantitative trait locus (QTL) on chromosome 6p21.3 for phonological decoding and orthographic choice deficits. Bivariate linkage analyses were then conducted to test the hypothesis that this QTL for reading difficulties is pleiotropic for slower performance on RN tasks. The results obtained from these analyses did not provide substantial evidence that the 6p QTL for reading difficulties has significant effects on rapid naming; however, larger samples would be required to test this hypothesis more rigorously.

The double-deficit hypothesis (Wolf, M. and Bowers, P.G. (1999) The double-deficit hypothesis for the developmental dyslexias. Journal of Educational Psychology, 91, 415-438) proposes that deficits in phonological processing and rapid automatized naming (RAN) are separable sources of reading dysfunction. Further, the double-deficit hypothesis predicts that the presence of deficits in both phonological processing and RAN have an additive negative influence on reading performance above and beyond that of a single deficit. The purpose of this study was to examine the additive nature of phonological awareness (PA)- and RAN-deficits on written language skill in children with reading disabilities (RD). Concurrent relationships between PA, RAN, and written language skills were examined in 476 children with RD, ranging in age from 8 to 18 years of age. Hierarchical regression analysis revealed that PA and RAN skill have an additive effect on a majority of the reading and spelling measures. When participants were classified into three deficit subtypes based on the double-deficit model (i.e. phonological-, rate-, and double-deficit), comparisons across the subtypes confirmed that individuals with double-deficits performed below the single-deficit groups on both subtyping variables (RAN and PA) and all measures of written language. When the double- and single-deficit groups were matched on the subtyping variable (i.e. double- and rate-deficit groups matched on RAN and double- and phonological-deficit groups matched on PA) differences between the double- and rate-deficit groups remained in non-word reading, whereas differences between the double- and phonological-deficit groups remained in timed word recognition and reading comprehension. These results support an additive model in which RAN-deficits primarily affect tasks that require speeded/fluent response, and PA-deficits primarily affect tasks that emphasize phonological processing skill. Results are also presented that illustrate several statistical problems associated with the formation of deficit groups by dichotomizing the RAN and PA variables.

This study utilized a sample of 313 eight- to sixteen-year-old same-sex twin pairs (183 monozygotic, 130 dizygotic) to assess the etiology of comorbidity between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD). RD was assessed by a discriminant function score based on the Peabody Individual Achievement Test, a standardized measure of academic achievement. The DSM-III version of the Diagnostic Interview for Children and Adolescents was used to assess symptoms of ADHD, and separate factor scores were computed for inattention and hyperactivity/impulsivity (hyp/imp). Individuals with RD were significantly more likely than individuals without RD to exhibit elevations on both symptom dimensions, but the difference was larger for inattention than hyp/imp. Behavior genetic analyses indicated that the bivariate heritability of RD and inattention was significant (h(2)(g(RD/Inatt)) = 0.39), whereas the bivariate heritability of RD and hyp/imp was minimal and nonsignificant (h(2)(g(RD/Hyp)) = 0.05). Approximately 95% of the phenotypic covariance between RD and symptoms of inattention was attributable to common genetic influences, whereas only 21% of the phenotypic overlap between RD and hyp/imp was due to the same genetic factors.

Parents of 323 twin pairs with reading disability (RD) reported significantly more problems learning to read (16% of mothers and 33% of fathers) than parents of 309 twin pairs without reading difficulties (6% of mothers and 9% of fathers). These rates of self-reported reading problems in parents of twins are highly similar to those previously obtained in parents of non-twin children with RD and controls, suggesting that the etiology of reading deficits in twin and non-twin children may also be highly similar. Moreover, within both the RD and control samples, twins whose parents self-reported a positive history of reading problems had lower reading performance test scores, on average, than those whose parents reported no reading problems. Therefore, results of the present twin study support those of previous studies with non-twin children in which parental self-reports have been found to provide a valid index of family history status for reading difficulties.

To test the hypothesis that the genetic etiology of reading disability differs as a function of IQ, composite reading performance data from 223 pairs of identical twins and 169 pairs of same-gender fraternal twins in which at least one member of each pair was classified with reading disability were subjected to multiple regression analysis (DeFries & Fulker, 1985, 1988). In the total sample, heritability of the group deficit in reading performance (h(g)2) was .58 (+/- .08). However, when the basic regression model was fitted separately to data from twin pairs with average Wechsler (1974, 1981) full scale IQ scores below 100 or 100 and above, resulting estimates of h(g)2 were .43 and .72, respectively, a significant difference (p < or = .03, one-tailed). The results of fitting extended regression models to reading performance and continuous IQ data provide evidence that the genetic etiology of reading disability differs as a linear function of IQ (p < or = .007, one-tailed). These results suggest that IQ is relevant for the diagnosis of reading disability and that environmental influences may be more salient as a cause of reading difficulties in children with lower IQ scores.

Although it is well known that there is considerable variation among individuals in the size of the human brain, the etiology of less extreme individual differences in brain size is largely unknown. We present here data from the first large twin sample (N=132 individuals) in which the size of brain structures has been measured. As part of an ongoing project examining the brain correlates of reading disability (RD), whole brain morphometric analyses of structural magnetic response image (MRI) scans were performed on a sample of adolescent twins. Specifically, there were 25 monozygotic (MZ) and 23 dizygotic (DZ) pairs in which at least one member of each pair had RD and 9 MZ and 9 DZ pairs in which neither member had RD. We first factor-analyzed volume data for 13 individual brain structures, comprising all of the neocortex and most of the subcortex. This analysis yielded two factors ("cortical" and "subcortical") that accounted for 64% of the variance. We next tested whether genetic and environmental influences on brain size variations varied for these two factors or by hemisphere. We computed intraclass correlations within MZ and DZ pairs in each sample for the cortical and subcortical factor scores, for left and right neocortex, and for the total cerebral volume. All five MZ correlations were substantial (r's=.78 to.98) and significant in both samples, as well as being larger than the corresponding DZ correlations, (r's=0.32 to 0.65) in both samples. The MZ-DZ difference was significant for 3 variables in the RD sample and for one variable in the smaller control sample. These results indicate significant genetic influences on these variables. The magnitude of genetic influence did not vary markedly either for the 2 factors or the 2 hemispheres. There was also a positive correlation between brain size and full-scale IQ, consistent with the results of earlier studies. The total cerebral volume was moderately correlated (r=.42, p<.01, two-tailed) with full-scale IQ in the RD sample; there was a similar trend in the smaller control sample (r=.31, p<.07, two-tailed). Corrections of similar magnitude were found between the subcortical factor and full-scale IQ, whereas the results for the cortical factor (r=.16 and.13) were smaller and not significant. In sum, these results provide evidence for the heritability of individual differences in brain size which do not vary markedly by hemisphere or for neocortex relative to subcortex. Since there are also correlations between brain size and full-scale IQ in this sample, it is possible that genetic influences on brain size partly contribute to individual differences in IQ.

The heritable nature of reading disability has been well documented (DeFries & Alarcón, 1996), and possible abnormalities of brain structures have been associated with the disorder (Filipek, 1995). However, the etiology of individual differences in morphological brain measures has not been examined extensively. The purpose of this study was to apply behavioral genetic methods to assess the etiology of individual differences in neuroanatomical structures. Measures of reading performance, cognitive ability, and magnetic resonance imaging scans were obtained from 25 monozygotic (MZ) and 23 same-sex dizygotic (DZ) twin pairs with reading disability, and 9 MZ and 9 DZ control twin pairs participating in the Colorado Learning Disabilities Research Center. Results obtained from multiple regression analyses (DeFries & Fulker, 1985, 1988) of these twin data indicated that individual differences in the size of most cortical and subcortical structures were largely due to heritable influences. Moreover, estimates of heritability did not change appreciably after controlling for IQ and total brain size.

Reading disability (RD), or dyslexia, is a complex cognitive disorder manifested by difficulties in learning to read, in otherwise normal individuals. Individuals with RD manifest deficits in several reading and language skills. Previous research has suggested the existence of a quantitative-trait locus (QTL) for RD on the short arm of chromosome 6. In the present study, RD subjects' performance in several measures of word recognition and component skills of orthographic coding, phonological decoding, and phoneme awareness were individually subjected to QTL analysis, with a new sample of 126 sib pairs, by means of a multipoint mapping method and eight informative DNA markers on chromosome 6 (D6S461, D6S276, D6S105, D6S306, D6S258, D6S439, D6S291, and D6S1019). The results indicate significant linkage across a distance of at least 5 cM for deficits in orthographic (LOD = 3.10) and phonological (LOD = 2.42) skills, confirming previous findings.

In recent years behavioral genetic studies have provided conclusive evidence that reading disability and related learning disorders, such as mathematics disability, are due at least in part to heritable factors (DeFries et al. 1987; Alarcón et al. 1997). Although the observed relationship between performance in these areas also may be due substantially to genetic influences (Light and DeFries 1995; Thompson et al. 1991), relatively few studies have examined the genetic and environmental etiology of this covariation in a multivariate framework. In the present study data from 196 identical (monozygotic; MZ) and 155 same-sex fraternal (dizygotic; DZ) twin pairs in which at least one member of each pair evidenced reading problems in school (reading disabled) were subjected to a multivariate behavioral genetic analysis. Structural equation models were fitted to twin data for verbal IQ (VIQ), phonological decoding ability (PHON), reading performance (READ), and mathematics performance (MATH) to assess the extent to which VIQ and PHON mediate the observed covariation between READ and MATH. Results suggest that VIQ and PHON account for most of the covariation between READ and MATH. Moreover, approximately 82% of the observed correlation between READ and MATH was due to genetic factors that also influence VIQ and PHON. When data from 132 MZ and 91 same-sex DZ control twin pairs in which neither twin had a history of reading problems were subjected to the same analyses, the covariation between READ and MATH was found to be due to both genetic and shared environmental influences. Thus genetic factors that influence VIQ and PHON also contribute to the observed covariation between READ and MATH in both a reading-disabled and a control twin sample.

We conducted a study of the association between developmental reading disability (DRD) and immune disorders (ID) using both survey and immunoassay data in two separate samples of families. One sample was made up of twins and their parents and was ascertained through a population-based sampling scheme. The other sample was a set of extended pedigrees selected for apparent autosomal dominant transmission of DRD. We failed to find an association between DRD and ID in either sample, regardless of the method used to assess immune system function. Even though our twin sample provided evidence that both DRD and immune conditions were significantly heritable, there was no evidence for a genetic correlation between ID and DRD nor was there any clear indication that a special subgroup of individuals may be comorbid for these conditions because of genetic reasons. How these negative findings can be reconciled with the developmental hypothesis of Geschwind, Behan, Galaburda, and colleagues, and how they may relate to the gene locus influencing DRD that has been recently located in the HLA region of the short arm of chromosome 6 is discussed., (Copyright 1998 Academic Press.)

In order to assess the genetic etiology of the comorbidity of reading and mathematics difficulties, data were ascertained from two samples: (1) 102 identical and 77 same-sex fraternal twin pairs in which at least one member of each pair is reading disabled and (2) 42 identical and 23 same-sex fraternal twin pairs in which at least one member is math disabled. Composite reading and mathematics performance data from each sample were fitted to the basic multiple regression model for the analysis of selected twin data and its bivariate extension. Resulting estimates of bivariate heritability and the genetic correlation between the reading and the mathematics performance measures suggest that the comorbidity between mathematics and reading difficulties is due in part to genetic influences.

Although children with learning disabilities frequently manifest comorbid reading and mathematics deficits, the cause of this comorbidity is unknown. To assess the extent to which comorbidity between reading and mathematics deficits is due to genetic and environmental influences, we conducted a twin study of reading and mathematics performance. Data from 148 identical and 111 fraternal twin pairs in which at least one member of the pair had a reading disability were subjected to a cross-concordance analysis and also fitted to a bivariate extension of the basic multiple regression model for the analysis of selected twin data. Results of these analyses suggest that genetic and shared-environmental influences both contribute to the observed covariance between reading and mathematics deficits.

Wechsler Intelligence Scale for Children--Revised (WISC-R) factor scores (Verbal Comprehension, Perceptual Organization, and Freedom from Distractibility) were obtained from 574 twin pairs in the Colorado Reading Project and subjected to multivariate genetic analysis. Variances were partitioned into components common to the three WISC-R factors and to those specific to each factor. Substantial commonality, both genetic and environmental, was found among the three factors. The full model fit the data well, and estimates of heritability and environmentality indicated that about half of the phenotypic variance for each factor is due to additive genetic effects. These results were compared to those obtained in a previous twin study of the three Wechsler Adult Intelligence Scale (WAIS) factors by Tambs et al. (1986).