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A three-stage genome-wide association study of general cognitive ability: hunting the small effects.

Davis OS, Butcher LM, Docherty SJ, Meaburn EL, Curtis CJ, Simpson MA, Schalkwyk LC, Plomin R - Behav. Genet. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK. Oliver.Davis@iop.kcl.ac.uk.

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.

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Quantile–quantile plots for samples 1 and 2. In each panel negative log base 10 P values from a mixed-effects model are plotted against theoretical quantiles from the  distribution. The straight line at x = y represents the  distribution and the gray areas represent 95% bootstrapped confidence intervals on the . The left-hand plot represents genome-wide SNPs passing quality control in sample 1; the right-hand plot represents the top 3,000 SNPs from sample 1 tested in sample 2 (one-tailed). Although the left-hand plot shows no associations greater than chance, the right-hand plot shows that the SNPs tested in the second sample are enriched for associations; this can be seen by the deviation of the SNPs from the x = y line. The best-performing SNPs from this second stage were individually genotyped in a large sample of TEDS individuals across the distribution of g and tested for quantitative association; the results are presented in Table 1
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Fig2: Quantile–quantile plots for samples 1 and 2. In each panel negative log base 10 P values from a mixed-effects model are plotted against theoretical quantiles from the distribution. The straight line at x = y represents the distribution and the gray areas represent 95% bootstrapped confidence intervals on the . The left-hand plot represents genome-wide SNPs passing quality control in sample 1; the right-hand plot represents the top 3,000 SNPs from sample 1 tested in sample 2 (one-tailed). Although the left-hand plot shows no associations greater than chance, the right-hand plot shows that the SNPs tested in the second sample are enriched for associations; this can be seen by the deviation of the SNPs from the x = y line. The best-performing SNPs from this second stage were individually genotyped in a large sample of TEDS individuals across the distribution of g and tested for quantitative association; the results are presented in Table 1

Mentions: Figure 1 shows genome-wide signal plots for the two pooling replication stages. Figure 2 shows that even though no SNPs stand out in a quantile–quantile plot of approximate P values from stage 1 of the study, selecting the top 3,000 SNPs for the second stage in a new sample results in SNPs enriched for lower P values.Fig. 1


A three-stage genome-wide association study of general cognitive ability: hunting the small effects.

Davis OS, Butcher LM, Docherty SJ, Meaburn EL, Curtis CJ, Simpson MA, Schalkwyk LC, Plomin R - Behav. Genet. (2010)

Quantile–quantile plots for samples 1 and 2. In each panel negative log base 10 P values from a mixed-effects model are plotted against theoretical quantiles from the  distribution. The straight line at x = y represents the  distribution and the gray areas represent 95% bootstrapped confidence intervals on the . The left-hand plot represents genome-wide SNPs passing quality control in sample 1; the right-hand plot represents the top 3,000 SNPs from sample 1 tested in sample 2 (one-tailed). Although the left-hand plot shows no associations greater than chance, the right-hand plot shows that the SNPs tested in the second sample are enriched for associations; this can be seen by the deviation of the SNPs from the x = y line. The best-performing SNPs from this second stage were individually genotyped in a large sample of TEDS individuals across the distribution of g and tested for quantitative association; the results are presented in Table 1
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2992848&req=5

Fig2: Quantile–quantile plots for samples 1 and 2. In each panel negative log base 10 P values from a mixed-effects model are plotted against theoretical quantiles from the distribution. The straight line at x = y represents the distribution and the gray areas represent 95% bootstrapped confidence intervals on the . The left-hand plot represents genome-wide SNPs passing quality control in sample 1; the right-hand plot represents the top 3,000 SNPs from sample 1 tested in sample 2 (one-tailed). Although the left-hand plot shows no associations greater than chance, the right-hand plot shows that the SNPs tested in the second sample are enriched for associations; this can be seen by the deviation of the SNPs from the x = y line. The best-performing SNPs from this second stage were individually genotyped in a large sample of TEDS individuals across the distribution of g and tested for quantitative association; the results are presented in Table 1
Mentions: Figure 1 shows genome-wide signal plots for the two pooling replication stages. Figure 2 shows that even though no SNPs stand out in a quantile–quantile plot of approximate P values from stage 1 of the study, selecting the top 3,000 SNPs for the second stage in a new sample results in SNPs enriched for lower P values.Fig. 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK. Oliver.Davis@iop.kcl.ac.uk.

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.

Show MeSH