John C. DeFries

Genotype-environment interaction and correlation in the analysis of human behavior.

Two issues that complicate behavioral genetic analyses are the interaction and correlation between genetic and environmental influences. In this report, the effects of genotype-envi ronment interaction and correlation on behavioral genetic studies (twin and adoption studies) are examined. The analysis suggests that genotype-environment interaction may bias twin study estimates of genetic and environmental influence, but need not affect adoption studies. On the other hand, genotype-environment correlation may affect both twin and adoption study estimates of genetic and environmental influence, the direction of the effect depending on the sign of the correlation. Finally, new tests of genotypeenvironment interaction and correlation, using adoption data, are proposed.

Individual Differences in Executive Functions Are Almost Entirely Genetic in Origin

Recent psychological and neuropsychological research suggests that executive functions--the cognitive control processes that regulate thought and action--are multifaceted and that different types of executive functions are correlated but separable. The present multivariate twin study of 3 executive functions (inhibiting dominant responses, updating working memory representations, and shifting between task sets), measured as latent variables, examined why people vary in these executive control abilities and why these abilities are correlated but separable from a behavioral genetic perspective. Results indicated that executive functions are correlated because they are influenced by a highly heritable (99%) common factor that goes beyond general intelligence or perceptual speed, and they are separable because of additional genetic influences unique to particular executive functions. This combination of general and specific genetic influences places executive functions among the most heritable psychological traits. These results highlight the potential of genetic approaches for uncovering the biological underpinnings of executive functions and suggest a need for examining multiple types of executive functions to distinguish different levels of genetic influences.

Not All Executive Functions Are Related to Intelligence

Accumulating evidence suggests that executive functions (EFs) are related to intelligence, despite neuropsychological results initially considered evidence of no such relation. However, findings that EFs are not unitary raise the issue of how intelligence relates to different EFs. This study examined the relations of fluid and crystallized intelligence and Wechsler Adult Intelligence Scale IQ to three separable EFs—inhibiting prepotent responses (inhibiting), shifting mental sets (shifting), and updating working memory (updating)—in young adults. Updating was highly correlated with the intelligence measures, but inhibiting and shifting were not. Furthermore, in structural equation models controlling for the inter-EF correlations, updating remained strongly related to intelligence, but the relations of inhibiting and shifting to intelligence were small and not significant. The results indicate that intelligence measures differentially relate to these three EFs, suggesting that current intelligence measures do not equally assess a wide range of executive control abilities likely required for many “intelligent” behaviors.

Multiple regression analysis of twin data

A multiple regression model for the analysis of twin data is described in which a cotwins score is predicted from a probands score and the coefficient of relationship (R=1.0 and 0.5 for identical and fraternal twin pairs, respectively). This model is especially appropriate for the analysis of data on twins in which one member of each pair has been selected because of a deviant score, e.g., low reading performance. When the model is fitted to such data, the partial regression of the cotwins score on the coefficient of relationship provides a powerful test of the extent to which the difference between the mean for probands and that for the unselected population is heritable, i.e., a test for genetic etiology. By fitting an augmented model containing an interaction term to either selected or unselected data sets, direct estimates of heritability and the proportion of variance due to shared environmental influences can also be obtained (subject, of course, to the usual assumptions underlying twin analyses, e.g., a linear polygenic model, little or no assortative mating, and equal shared environmental influences for identical and fraternal twins).

A simple genetic basis for a complex psychological trait in laboratory mice.

Psychological traits are commonly inferred from covariation in sets of behavioral measures that otherwise appear to have little in common. Emotionality in mice is such a trait, defined here by covariation in activity and defecation in a novel environment and emergence into the open arms of an elevated plus maze. Behavioral and quantitative trait analyses were conducted on four measures obtained from 879 mice from an F2 intercross. Three loci, on murine chromosomes 1, 12, and 15, were mapped that influence emotionality. This trait, inferred from studies of strain, sex, and individual differences in rodents, may be related to human susceptibility to anxiety or neuroticism.

The heritability of general cognitive ability increases linearly from childhood to young adulthood

Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite lifes ‘slings and arrows of outrageous fortune’, do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype–environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.

Developmental dyslexia: genetic dissection of a complex cognitive trait

Developmental dyslexia, a specific impairment of reading ability despite adequate intelligence and educational opportunity, is one of the most frequent childhood disorders. Since the first documented cases at the beginning of the last century, it has become increasingly apparent that the reading problems of people with dyslexia form part of a heritable neurobiological syndrome. As for most cognitive and behavioural traits, phenotypic definition is fraught with difficulties and the genetic basis is complex, making the isolation of genetic risk factors a formidable challenge. Against such a background, it is notable that several recent studies have reported the localization of genes that influence dyslexia and other language-related traits. These investigations exploit novel research approaches that are relevant to many areas of human neurogenetics.

Multiple regression analysis of twin data: etiology of deviant scores versus individual differences.

The multiple regression analysis of twin data in which a cotwins score is predicted from a probands 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.

Response to 30 generations of selection for open-field activity in laboratory mice.

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 lowactive 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.

Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia

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≤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.