Genetics Molecular of Attention
MARK A. BELLGROVE AND JASON B. MATTINGLEY
School of Psychology and the Queensland Brain Institute, University of Queensland, Australia
The sequencing of the human genome and the identification of a vast array of DNA polymorphisms has afforded cognitive scientists with the opportunity to interrogate the genetic basis of cognition with renewed vigor. The extant literature on the molecular genetics of sustained and spatial attention is reviewed herein. Advances in our understanding of the neural substrates of sustained and spatial attention arising from the cognitive neurosciences can help guide putative linkages in cognitive genetics. In line with catecholamine models of sustained attention, associations have been reported between sustained attention and allelic variation in the dopamine beta hydroxylase gene (DBH), the dopamine D2 and D4 receptor genes (DRD2; DRD4) and the dopamine transporter gene (DAT1). Much evidence implicates the cholinergic system in spatial attention. Accordingly, individual differences in spatial attention have been associated with variation in an alpha-4 cholinergic receptor gene (CHRNA4). APOE-4 allele dosage has been shown to influence the speed of attentional reorienting in independent samples of nonaffected individuals. Preliminary evidence in both healthy children and children with attention deficit hyperactivity disorder (ADHD) suggests and association with variants of the DAT1 gene and the control of spatial attention across the hemifields. With the recent development of high-throughput genotyping techniques, such as microarrays, the time seems ripe for a genomewide association study that can identify quantitative trait loci (QTLs) for sustained and spatial attention. The identification of QTLs for attention will provide a range of novel candidate genes for disorders of attention, such as ADHD and schizophrenia, and will drive cognitive neuroscientists to understand how DNA variation influences the neural substrates of attention. Key words: attention; sustained attention; spatial attention; genetics; dopamine; APOE; acetylcholine; ADHD; DAT1; DRD4
Introduction
Science has long sought to determine whether individual differences in cognitive capacity can be ascribed to differences in underlying genetics. In the past, behavior genetics addressed this question by parsing the genetic and environmental contributions to cognition using the classic twin design. These studies have clearly achieved much by showing that complex cognition, as assessed, for example, by general intelligence measures, such as "g," is strongly influenced by genes.1 More recently this endeavor has gained new impetus with the sequencing of the human genome, so that scientists can now ask how variation within a specific gene influences individual differences in a specific cognitive process. These advances in molecular genetics have provided those working in cognitive neuroscience with the opportunity to interrogate old questions in entirely new ways
Address for correspondence: Mark A. Bellgrove, Ph.D., School of Psychology, University of Queensland, 4072 Queensland, Australia. [e-mail]
and allow the testing of cognitive models at a new level of analysis. The application of molecular genetics to studies of cognition--cognitive genetics--follows strongly in the tradition of cognitive neuropsychology.2 In the latter, the effects of localized cerebral lesions on specific cognitive functions have thrown considerable light on the cognitive architecture of the normally functioning human brain.3 For example, the syndrome of unilateral spatial neglect, in which patients display deficits in detecting and acting upon contralesional stimuli is most frequent and severe following lesions centered on the posterior parietal lobe of the right cerebral hemisphere.4 The central role played by this region in human spatial attention has been confirmed by numerous neuroimaging studies with healthy participants who have shown activity in the right temporoparietal junction, particularly when observers must shift their attention from an invalidly cued location to detect a target at a contralateral location.5,6 In the case of cognitive genetics, specific allelic variants of candidate genes (see TABLE 1) take the place of specific cerebral lesions, and so a linkage is made between
Ann. N.Y. Acad. Sci. 1129: 200212 (2008). doi: 10.1196/annals.1417.013
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Bellgrove & Mattingley: Molecular Genetics of Attention
TABLE 1. Glossary of terms Term Allele Definition
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An alternative form of a gene that can occur at a given locus on a gene. Alleles differ in their nucleotide sequence. A single allele for each locus of a gene is inherited from each parent. Candidate gene A gene located on a chromosomal region that is thought to be involved in a trait (e.g., cognitive process) or a disorder (e.g., ADHD). Candidate genes are normally chosen based on prior physiological, genetic, or biochemical characterisation that leads one to suspect that this gene is involved in the trait. Haplotype A set of closely linked alleles inherited as a unit. These linked SNPs may be useful in defining a haplotype block that may harbor a causative variant for a trait. Intron A nucleotide sequence in a gene that does not code for the gene product. Introns can be compared to exons, which are the protein-coding portion of a gene. Linkage disequilibrium (LD) LD occurs when alleles at different loci occur together within an individual at a greater than chance frequency. Single nucleotide polymorphism (SNP) Different versions of a gene, due to differences in nucleotides on DNA, are called polymorphisms. The most common form of genetic variation, the SNP, reflects a change in a single base in the DNA that differs from the usual base at that position. Adapted from Bellgrove et al.2
cognitive functions on the one h...
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