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Objective: --There is strong evidence that developmental dyslexia is both familial and heritable, but the mode of genetic transmission has remained unclear. In this article, we examine specific genetic hypotheses about the mode of transmission of developmental dyslexia by performing complex segregation analyses., Design: --A family study method was applied, whereby the relatives of dyslexic probands were examined for dyslexia. The families studied represent four independently ascertained samples., Setting: --The four samples of families were primarily from rural and suburban communities of Colorado, Washington State, and Iowa., Participants: --A total of 204 families and 1698 individuals in the four samples combined., Main Outcome Measures: --The complex segregation program, POINTER, was used to test competing genetic hypotheses of how a categorical trait (dyslexia) is transmitted in families., Results: --The results were consistent with major locus transmission in three of four samples and with polygenic transmission in the fourth. In these three samples, the estimates of penetrance for the AA, Aa, and aa genotypes (where A is the abnormal allele) were, respectively, 1.000, 1.000, and 0.001 to 0.039 in males, and 0.560 to 1.000, 0.550 to 0.897, and 0.000 in females. The estimated gene frequency of the major locus was between 3% and 5%., Conclusions: --Sex-influenced, additive, or dominant transmission occurs in a significant proportion of dyslexic families. Other evidence indicates, however, that dyslexia is etiologically heterogeneous and that there is genetic heterogeneity even among families selected for apparent dominant transmission. Thus, while no single major locus may account for all of dyslexia, it is important to pursue potential major loci for dyslexia using linkage techniques.

Gender differences were assessed in three research-identified samples of children who were members of twin pairs: (1) 120 male and 124 female probands from same-sex identical and fraternal twin pairs in which at least one member of each pair is reading disabled; (2) a comparison sample of 148 males and 161 females from same-sex twin pairs with no history of reading problems; and (3) 34 pairs of opposite-sex fraternal twin pairs in which at least one member of each pair is reading disabled. Results of multivariate analyses of variance of psychometric test data from the two samples of same-sex twin pairs, in which the male and female subjects were reared in different homes, suggest that profiles of gender differences are similar in reading-disabled and control children. Moreover, this pattern of gender differences also tended to occur in opposite-sex twin pairs, who shared prenatal, as well as early postnatal, environmental influences. In general, reading-disabled males obtained higher average scores than affected females on Wechsler (1974, 1981) Verbal and Performance IQ, but lower scores on Reading Recognition and Spelling subtests of the Peabody Individual Achievement Test (Dunn and Markwardt 1970). With regard to the Wechsler subtests, reading-disabled males achieved higher average scores on Information, Picture Completion, Block Design, and Object Assembly, but lower scores on Coding. Although significant and relatively consistent gender differences in cognitive measures were found in three samples included in this study, these differences account for only a small portion of the observed variance.

The multiple regression analysis of twin data in which a cotwin's score is predicted from that of a proband (the member of a twin pair selected because of a deviant score) and the coefficient of relationship provides a powerful test of genetic etiology (DeFries and Fulker: Behav Genet 15:467-473, 1985). Moreover, when an augmented model containing an interaction term is fitted to the same data set, direct estimates of heritability (h2) and the proportion of variance owing to shared environmental influences (c2) are also obtained. In the present paper, the expected partial regression coefficients estimated from these models are derived, and the flexibility of the general approach is illustrated. An extended model is formulated for the analysis of data from combined samples of affected and control twin pairs that yields tests for differential h2 and c2 in the two groups as well as pooled estimates of these parameters. The application of these models is illustrated by an analysis of data from reading-disabled and control twin pairs. Because of the ease, flexibility, and utility of the multiple regression analysis of twin data, it is an appealing alternative to more traditional model-fitting approaches.

Multivariate path analysis is employed to examine the etiologies of variation and covariation of three composite cognitive measures in the Colorado Family Reading Study: reading ability, symbol-processing speed, and spatial/reasoning. Measures of phenotypic assortative and cross-assortative mating are incorporated in a multivariate analysis of familial resemblance within nuclear families. Phenotypic variances and covariances are partitioned into components due to familial (genetic and/or family environmental) influences and to specific, nontransmissible environmental influences in families with a reading-disabled child as well as families with children of normal reading ability. Comparable moderate familial influences are found across family type for all three composites and the phenotypic correlations between traits are largely due to familial influences.

Test data collected on 133 reading-disabled (RD) children and their nuclear families who participated in the Colorado Family Reading Study were subjected to segregation analysis utilizing the technique of Elston and Yelverton (1975) for a continuous phenotypic measure. The possibility of genetic heterogeneity of RD was investigated by analyzing four subsets of data: all families, families with male probands, families with female probands, and families with severely affected probands. Furthermore, an analysis of the children's data was compared to that of all family members to investigate the possibility that the disorder may be manifested differently in adults. Results from the four subsets of data show that RD is etiologically heterogeneous. Compatibility with a major recessive gene for RD was demonstrated for families with female probands. Analyses of the children's data alone give results consistent with both environmental and genetic determination of RD.

Adoption studies can provide direct evidence for the independent effects of family environment and heredity that are always confounded in intact nuclear families. When children are separated from their biological mothers shortly after birth and placed nonselectively in adoptive homes, adoptive-parent/adopted-child resemblance can be ascribed to cultural transmission, whereas biological-parent/adopted-child similarities are due to heritable factors. Furthermore, a longitudinal adoption study facilitates examination of changes in these two main sources of variation during development. The Colorado Adoption Project is the first large-scale longitudinal adoption study of behavioural development and was initiated in 1975. Data were collected from biological parents of 245 adopted children, the adoptive parents and parents of 245 matched nonadopted children. The children have subsequently been tested at 1, 2, 3 and 4 years of age, and at the end of their first year in primary school (average age, 7.4 years). The number of subjects tested is now adequate for analysis of data over 7 years. The results provide conclusive evidence for increasing heritable variation of general mental ability, ranging from 9% at 1 year of age to 36% at 7 years.

Longitudinal psychometric test data collected at two different ages (9.4 +/- 1.3 and 14.8 +/- 1.2 years) were utilized to compare the developmental rates of 69 pairs of reading-disabled and matched control children. Results of a two-factor (GROUP X TIME), mixed-model, multivariate analysis of variance indicated that reading-disabled children manifested deficits on measures of academic achievement, symbolic processing speed and spatial reasoning abilities at both ages. Although both reading-disabled and control children were found to improve significantly between the two testing sessions, the lack of a significant GROUP X TIME interaction on measures of academic achievement and spatial reasoning abilities indicated that the rate of development was similar for the two groups. For measures of symbolic processing speed, however, differences between reading-disabled and control children were somewhat greater at the later age.

Evidence for the heterogeneity of reading disability was sought in a family study. Psychometric test data on 125 reading-disabled children (probands) and their siblings and parents were used to identify four subtypes of reading disability, each with a distinctive cognitive ability profile. The validity of this profile analysis was then assessed by applying the same classification system to profiles of affected parents and siblings of the probands. Affected siblings of probands in subtype 3 (severely impaired reading ability but normal spatial/reasoning and coding/speed) were more likely to be of the same subtype than would be expected on the basis of chance. However, no such evidence for familial transmission of specific subtypes was found in the parental data. It is suggested that family studies may provide a strong test of the heterogeneity of reading disability, and that such studies should be used to assess the validity of alternative typologies.

Several researchers have recently attempted to apply factor analytic procedures to genetic data. These attempts, however, have been unsystematic. The application of component analysis to phenotypic, genetic and environmental correlation matrices is discussed in this paper. Formulas for computing phenotypic, genetic and environmental component scores are given. The interpretation of factors is discussed and a worked example is included.

Mice selectively bred for differences in open-field activity were utilized to test the hypothesis that differences in open-field behaviour are mediated at least in part by components of the GABA system, including brain glutamic acid decarboxylase activity (V, Vmax, and Km), as well as glutamate and GABA concentrations. Enzyme velocity was found to be inversely correlated with open-field activity, but it accounted for less than 15% of the variance. Moreover, the rank order of the lines was not as predicted for a genetically correlated character and the magnitude of the differences in enzyme activity among the lines was not large. It was therefore concluded that the GABA system is not an important mediator of differences in open-field behaviour in these lines of mice.

In order to assess the genetic correlates of differences in ethanol-induced anesthesia, a set of 27 recombinant inbred (RI) strains was derived from an initial cross of the "long-sleep" (LS) and "short-sleep" (SS) selected lines of mice. In generations F24 and F25, samples of 534 and 580 mice from the LSXSS RI strains were tested for fall time, sleep time, and blood ethanol at awakening subsequent to intraperitoneal injection of a 4.1-g/kg body weight dose of ethanol. Approximately 2 weeks later, mice from F24 were also tested for body temperature lowering and blood-ethanol elimination rate (beta 60). Differences among the average ethanol-induced sleep-time scores of the RI strains are large (ranging from 36 to 171 min) and account for over 50% of the observed variance. Effects due to generation, sex, litters within strains, and the interaction between strain and generation are also significant, but account for relatively small proportions of the total variance. Quantitative genetic analyses of these data suggest that differences in sleep-time scores are polygenic; however, allelic differences at the albino (c) locus may have a pleiotropic effect. Genetic correlations between sleep time and blood ethanol at awakening (-0.79) and between body temperature 60 min after injection and beta 60 (+0.48) are significant. Because differences among the LSXSS RI strains are large and highly reliable, they should be valuable animal models for testing more searching hypotheses about the etiology of individual differences in ethanol-induced anesthesia.

This report provides an overview of the Colorado Adoption Project (CAP), a longitudinal, prospective, multivariate adoption study of behavioral development. Examples of the types of analyses that can be conducted using this design are presented. The examples are based on general cognitive-ability data for adoptive, biological, and control parents; assessments of their home environment; and Bayley Mental Development Index scores for 152 adopted children and 120 matched control children tested at both 1 and 2 years of age. The illustrative analyses include matched control children tested at both 1 and 2 years of age. The illustrative analyses include examination of genetic and environmental sources of variance, identification of environmental influence devoid of genetic bias, assessment of genotype-environment interaction and correlation, and analyses of the etiology of change and continuity in development.

A multivariate path model of genetic and environmental transmission employing a conditional path representation of assortative mating was fitted to specific cognitive abilities data from the Colorado Adoption Project and evaluated using a maximum-likelihood estimation procedure. In agreement with results obtained from a previous analysis of a smaller data set, significant genetic covariation among the cognitive variables was indicated and evidence for a general genetic factor was found. However, cultural transmission parameters are nonsignificant and environmental correlations among the measures are relatively small.

An extensive psychometric test battery was administered to 125 children with a reading disability, to their parents and siblings, and to members of 125 matched control familes (N = 1,044). In addition to expected differences in spelling and reading, probands obtained significantly (P less than or equal to .01) lower scores than controls on tests of other cognitive abilities. Manifold deficits were also found in siblings and parents of probands, conclusively demonstrating the familial (genetic and/or common-family environmental) nature of the disorder.

The open-field behavior of 719 mice resulting from a diallel cross among the six lines of the DeFries selection experiment was assessed. Results of several analyses employing different models and procedures in open-field activity and defecation among these lines have predominantly additive effects. Estimates of heritability obtained from these analyses were considerably higher than previous estimates based on familial resemblance or the realized response to selection; thus estimation of heritability from diallel analyses is clearly unwarranted when selected lines are employed and the character of interest has been either directly or indirectly subjected to artificial selection.

Data on reading-disabled and control probands and their families tested in the Colorado Family Reading Study were subjected to a comprehensive longitudinal-familial path analysis. Covariance matrices were constructed from composite scores for reading performance and for coding and symbol processing speed, and maximum likelihood estimates of familial parameters were obtained. With regard to the reading data, these estimates suggest that parental influences contribute importantly to longitudinal stability for reading-disabled children but not for controls. Such a difference in covariance structure between the 2 types of families could be due to a gene (or genes) with major effect. In the case of coding and symbol processing speed, covariance structure is similar for the 2 types of families, and combined parameter estimates indicate that parental contributions to longitudinal stability for this measure are relatively unimportant.

Previous twin studies of reading disability employed a comparison of concordance rates in identical and fraternal twin pairs as a test for genetic etiology. Recently, a statistically more powerful multiple regression analysis of twin data has been formulated to assess the importance of genetic factors in the development of reading difficulties. Application of this analysis to twin data from the Colorado Reading Project yields definitive evidence for a genetic etiology. Results from this study suggest that approximately 40 percent of the deficit observed in the disabled readers is due to genetic factors, 35 percent is due to environmental influences shared by members of twin pairs, and about 25 percent is the result of environmental factors unique to the individual and/or error variance.

A path model of genetic and shared family environmental transmission was fitted to general cognitive ability data from 1-, 2-, 3-, and 4-year-old adopted and nonadopted children and their parents in order to assess the etiology of longitudinal stability from infancy to early childhood. Stability across years is moderate and is due mainly to influences not predicted by parental IQ. Results of the present study, in conjunction with those of previous twin studies, suggest substantial genetic stability from infancy and early childhood to adulthood.

High and low lines resulting from 30 generations of bidirectional selection for open-field activity have nonoverlapping distributions and more than a thirtyfold difference in mean activity. Open-field defecation scores of low-active lines are approximately 7 times higher than those of high-active lines, substantiating earlier reports of a large, negative genetic correlation between these characters. Since the selection experiment is replicated, other variables which are found to be reliably different among the high, control, and low lines are likely to be causally related to open-field activity; thus these selected lines of mice may be of use to other investigators.

The multiple regression analysis of twin data in which a cotwin's score is predicted from a proband's score and the coefficient of relationship (the basic model) provides a statistically powerful test of genetic etiology. When an augmented model that also contains an interaction term is fitted to the same data set, direct estimates of heritability (h2) and the proportion of variance due to shared environmental influences (c2) are obtained. A simple transformation of selected twin data prior to regression analysis facilitates direct estimates of h2g (an index of the extent to which the difference between the mean of probands and that of the unselected population is heritable) and a test of the hypothesis that the etiology of deviant scores differs from that of variation within the normal range.

Regressions of offspring on midparent value for tests of specific cognitive abilities in Korea were considerably higher than those for Americans of Japanese ancestry or Americans of European ancestry tested in Hawaii. This greater parent-offspring resemblance in Korea may be due to the particular method of test administration or to an increased genetic variance resulting from assortative mating. The pattern of parent-child correlations for three relatively pure tests of spatial ability and for the spatial factor did not conform to that of a sex-linked recessive character.

Measures of general cognitive ability in 1- and 2-year-old adopted and nonadopted infants and their parents were subjected to path analysis to estimate the contribution of genetic and environmental factors to short-term stability. Although significant genetic influences were found at both 1 and 2 years of age, no significant environmental influences shared by parents and children were observed at these ages. Short-term stability of mental ability between the 2 ages was relatively independent of both between-family genetic and environmental influences. However, genetic factors may contribute importantly to long-term stability.

Reading disability (dyslexia) is a major social, educational, and mental health problem. Although estimates of prevalence vary, up to 10-15% of school-age children have severe reading deficits in spite of average intelligence and adequate educational opportunity. That reading disability may have a constitutional basis has long been recognized, and results of twin and family studies suggest that one or more of its forms may be heritable; however, definitive evidence for a genetic aetiology has not been reported. Establishing a heritable basis for reading disability could suggest possible causes, give improved risk estimates, facilitate early diagnosis, and provide validity tests for ostensible subtypes. In this report, we apply a recently developed multiple regression analysis to data collected from a sample of 64 pairs of identical twins and 55 pairs of fraternal twins, in which at least one member of the pairs is reading disabled, and present evidence for a significant genetic aetiology.

Extensive psychometric test data were obtained from two independent samples of reading-disabled and control children: 70 probands and 75 controls tested on two occasions over an average interval of 4.2 years, and 35 probands and 22 controls tested on three occasions over an average interval of 8.6 years. When composite measures of reading performance and symbol-processing speed were subjected to mixed-model multivariate analyses of variance, significant effects due to group (reading-disabled versus control) and time (i.e., test session) were obtained in both samples, and a significant group-by-time interaction was obtained for the sample tested on three occasions. In general, rates of change in reading performance are highly similar for reading-disabled and control children. However, with regard to symbol-processing speed, differences between the two groups increase as a function of age. Although no evidence was obtained for differential longitudinal stability of either composite measure in reading-disabled and control children, results of a multiple regression analysis suggest that reading deficits during middle childhood are highly predictive of later reading problems, even into early adulthood.

The Identical Blocks Test of spatial ability was administered to subsamples of the two largest ethnic groups tested in the Hawaii Family Study of Cognition--Americans of European ancestry (171 families) and Americans of Japanese ancestry (98 families). Results of a hierarchical multiple regression analysis of family data and correlational analyses provided no evidence to support the hypothesis that spatial ability is influenced by a major, X-linked, recessive gene. Thus it appears that recent failures to replicate the sex-linkage pattern obtained by Stafford (1961) are not due to differences in the tests employed. We suggest that alternative explanations should be sought for the well-known sex difference in spatial ability.

Multivariate behavioral genetic analyses may employ either genetic and environmental correlations or phenotypically standardized covariances to assess the structure of genetic and environmental influences. Correlations and phenotypically standardized covariances answer different questions--correlations are appropriate for understanding the nature of genetic and environmental influences, whereas covariances are appropriate for determining the etiology of phenotypic correlations. The ratio of the genetic and environmental covariances to the phenotypic correlation yields estimates of bivariate heritability and environmentality, measures of the extent to which observed phenotypic covariance is due to genetic and environmental influences. Multivariate analyses of genetic and environmental correlations and covariances are illustrated with twin data on scholastic abilities. Factor analyses of correlations suggest that the same set of genes affects the major areas of academic achievement and that the environmental influences are similarly structured. Analyses of phenotypically standardized covariances indicate that the structures of genetic and environmental influences as they contribute to phenotypic resemblance among scholastic abilities are both similar and simple: there are one general genetic factor and one general environmental factor. Bivariate heritabilities and environmentalities are similar in magnitude, indicating that the strong phenotypic relationship among scholastic abilities is due roughly equally o genetic and environmental influences.