, Volume 40, Issue 6, pp 759-767,
Open Access This content is freely available online to anyone, anywhere at any time.
Date: 21 Mar 2010

A Three-Stage Genome-Wide Association Study of General Cognitive Ability: Hunting the Small Effects

Abstract

Childhood general cognitive ability (g) is important for a wide range of outcomes in later life, from school achievement to occupational success and life expectancy. Large-scale association studies will be essential in the quest to identify variants that make up the substantial genetic component implicated by quantitative genetic studies. We conducted a three-stage genome-wide association study for general cognitive ability using over 350,000 single nucleotide polymorphisms (SNPs) in the quantitative extremes of a population sample of 7,900 7-year-old children from the UK Twins Early Development Study. Using two DNA pooling stages to enrich true positives, each of around 1,000 children selected from the extremes of the distribution, and a third individual genotyping stage of over 3,000 children to test for quantitative associations across the normal range, we aimed to home in on genes of small effect. Genome-wide results suggested that our approach was successful in enriching true associations and 28 SNPs were taken forward to individual genotyping in an unselected population sample. However, although we found an enrichment of low P values and identified nine SNPs nominally associated with g (P < 0.05) that show interesting characteristics for follow-up, further replication will be necessary to meet rigorous standards of association. These replications may take advantage of SNP sets to overcome limitations of statistical power. Despite our large sample size and three-stage design, the genes associated with childhood g remain tantalizingly beyond our current reach, providing further evidence for the small effect sizes of individual loci. Larger samples, denser arrays and multiple replications will be necessary in the hunt for the genetic variants that influence human cognitive ability.

Edited by George Vogler.
This paper originated from a talk given by Robert Plomin at a festschrift in honor of Gerald E. McClearn on May 9, 2009 at the Pennsylvania State University. Jerry’s career reflects the coming together of the two worlds of genetics—quantitative genetics and molecular genetics. Genome-wide association studies contribute to this merger, although the most notable finding so far, as represented in this paper, is that we are a long way from identifying all of the genes responsible for the heritability of complex traits like general cognitive ability. Jerry began his training as a quantitative geneticist just as Crick and Watson discovered the DNA basis of molecular genetics. His most cited contributions involve creative uses of quantitative genetic techniques in both mouse and human studies that paved the way for molecular genetic attempts to identify the specific genes responsible for the genetic effects he discovered. In mice, he used the experimental power of the selection design to demonstrate the importance of genetic influence in alcohol preference (e.g., McClearn and Rodgers 1959) and alcohol sensitivity (e.g., McClearn and Kakihana 1973) which created animal models that have greatly advanced the field of pharmacogenetics and have also been widely used in molecular genetic research (Crabbe 2002). His work on recombinant inbred strains of mice is an early example of merging quantitative genetics and molecular genetics (McClearn et al. 1991). Most apropos to molecular genetic research on complex traits is his long-term interest in integrative genetics and the application of systems biology (McClearn 2006), which we predict will be increasingly important as genome-wide association studies such as ours begin to identify some of the many genes of small effect that are associated with complex traits and common disorders. We dedicate this paper to him.