Progress in the Molecular- Genetic Study of Intelligence

The past decade has seen a major shift in the genetic study of human intelligence; where classic studies aimed to quantify the heritability of intelligence, current studies aim to dissect this heritability into its molecular-genetic components. Five whole-genome linkage scans have been published in the past year, converging on several chromosomal (or genomic) regions important to intelligence. A handful of candidate genes, some of which lie in these genomic regions, have shown significant association to intelligence and the associations have been replicated in independent samples. Finding genes brings us closer to an understanding of the neurophysiological basis of human cognition. Furthermore, when genes are no longer latent factors in our models but can actually be measured, it becomes feasible to identify those environmental factors that interact and correlate with genetic makeup. This will supplant the long nature–nurture debate with actual understanding. KEYWORDS—cognition; quantitative trait locus; gene– environment interaction; gene–environment correlation Individual performance on a single aspect of cognitive ability is highly predictive of performance on other aspects of cognitive ability. About 40% of the variance in multiple aspects of cognitive ability can be accounted for by a single general-intelligence factor. Genetic analyses of data obtained from monozygotic (from a single egg) and dizygotic (from different eggs) twin pairs indicate that this general-intelligence factor is highly heritable. Estimates range from 40% in childhood to 80% in late adulthood. In keeping with the postulate of a generalintelligence factor, substantial genetic overlap is found not only between different aspects of cognitive ability (such as reading ability, working memory, and attention) but also between different biological levels of cognitive ability, such as brain size or protein levels. This observation has led to the recent formulation of the ‘‘generalist genes’’ hypothesis, which states that the same genes affect multiple cognitive abilities (Plomin and Kovas, 2005). In recent years, molecular-genetic studies have indeed started to identify these genes, with the full awareness that they are ‘‘polygenes’’—i.e., they may each explain only a very small part of the variation in one or more cognitive abilities. The generalistgenes hypothesis also implies that cognitive disabilities are the extremes of normally distributed dimensions of cognitive abilities. Therefore, exactly those genes that have been associated with normal cognitive abilities could provide important clues to underlying mechanisms of milder but more prevalent forms of impaired cognitive functioning, like reading disorder, dyslexia, and attention deficit hyperactivity disorder, or even the severe cognitive deficits seen in autism and schizophrenia. GENE-FINDING STRATEGIES To identify genes underlying genetic variation in intelligence, two main strategies are available: linkage analysis and candidate-gene association studies. In linkage analysis, a number of DNA markers of known location, evenly dispersed throughout the entire set of chromosomes (the genome), are measured in genetically related individuals. DNA markers can be mutations in a single base pair (the smallest unit of the DNA helix; such mutations are called single nucleotide polymorphisms, SNPs) or a variable number of repeats of two or more base pairs (microsatellites). They need not be part of a functional gene—they are merely landmarks in the genome. For each DNA marker, evidence for linkage to a particular trait, like cognitive ability, is obtained through statistical procedures that trace how often the trait and the DNA marker are jointly passed along in familial lineages (cosegregation). If such a cosegregation of a DNA Address correspondence to Danielle Posthuma, Vrije Universiteit Amsterdam, Department of Biological Psychology, van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands; e-mail: [email protected]. The heritability of a trait is a ratio of the genetic variance to the total variance of that trait, so changes in heritability can be the result of changes in environmental variation or in genetic variation. The latter in turn may be caused by the same genes having differential effects across different ages (gene amplification) or by genes turning on and off at certain points in development (gene emergence). CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE Volume 15—Number 4 151 Copyright r 2006 Association for Psychological Science marker and a trait can be established with sufficient statistical confidence, then one or more genes in the vicinity of the marker are possibly involved in trait similarity among individuals, because genetic material on chromosomes is passed on in chunks. Linkage analysis thus serves to detect the regions (called quantitative trait loci) of the genome where genetic variants with a quantitative effect on the trait must be located. The first whole-genome linkage scan for intelligence was published in 2005 (Posthuma et al., 2005), and four more studies have been published since (Buyske et al., 2006; Dick et al., 2006; Luciano et al., 2006; Wainwright et al., 2006). The sample used in the first study consisted of a Dutch sample (159 sibling pairs) and an Australian sample (475 sibling pairs). Results indicated two areas of significant linkage to general intelligence—one on the long arm (denoted as q) of chromosome 2 (i.e., 2q) and one on the short arm (denoted as p) of chromosome 6 (i.e., 6p)—and several areas of suggestive linkage (an additional site on 2q, as well as areas on 4p, 7q, 20p, and 21p). The chromosome-2 area has been implicated in linkage scans for autism and dyslexia, while the chromosome-6 area is the main linkage area for reading ability and dyslexia. Two studies with a partly overlapping sample confirmed the importance of the areas on chromosomes 2 and 6 for specific aspects of intelligence (Luciano et al., 2006) as well as for academic achievement, which is different from IQ score but predicts IQ very well (correlation around 0.6; Wainwright et al., 2006). The Luciano et al., (2006) study additionally showed that both word recognition and IQ were linked to chromosome 2, confirming the notion of the same genes influencing different aspects of cognitive ability (Plomin and Kovas, 2005). A completely independent study by Dick et al. (2006) using data collected as part of the Collaborative Study on the Genetics of Alcoholism (COGA) also confirmed linkage of intelligence to the chromosome-6 area. A second scan based on that dataset (Buyske et al., 2006) found strong evidence for linkage of specific cognitive abilities to chromosome 14, an area that showed suggestive evidence for linkage in three of the five linkage studies (see Fig. 1). Although the COGA dataset has been selected for alcohol dependence and may thus not be representative of the general population, Dick et al. (2006) showed that alcohol dependence explained less than 1% of the variance in IQ scores. Moreover, a correction for the selection strategy used e e