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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.

SUBMITTER: Davis OS

PROVIDER: S-EPMC2992848 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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

Davis Oliver S P OS Butcher Lee M LM Docherty Sophia J SJ Meaburn Emma L EL Curtis Charles J C CJ Simpson Michael A MA Schalkwyk Leonard C LC Plomin Robert R

Behavior genetics 20100321 6

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 quantit ...[more]

PMID: 20306291

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Project description:BackgroundInfections and activated immune responses can affect the brain through several pathways that might also affect cognition. However, no large-scale study has previously investigated the effect of infections on the general cognitive ability in the general population.MethodsDanish nationwide registers were linked to establish a cohort of all 161,696 male conscripts during the years 2006-2012 who were tested for cognitive ability, which was based on logical, verbal, numerical and spatial reasoning at a mean age of 19.4 years. Test scores were converted to a mean of 100.00 and with a standard deviation (SD) of 15. Data were analyzed as a cohort study with severe infections requiring hospitalization as exposure using linear regression.ResultsAdjusted effect sizes were calculated with non-exposure to severe infections as reference, ranging from 0.12 SD to 0.63 SD on general cognitive ability. A prior infection was associated with significantly lower cognitive ability by a mean of 1.76 (95%CI: -1.92 to -1.61; corresponding to 0.12 SD). The cognitive ability was affected the most by the temporal proximity of the last infection (P<0.001) and by the severity of infection measured by days of admission (P<0.001). The number of infections were associated with decreased cognitive ability in a dose-response relationship, and highest mean differences were found for ≥10 hospital contacts for infections (Mean: -5.54; 95%CI: -7.20 to -3.89; corresponding to 0.37 SD), and for ≥5 different types of infections (Mean: -9.44; 95%CI: -13.2 to -5.69; corresponding to 0.63 SD). Hospital contacts with infections had occurred in 35% of the individuals prior to conscription.ConclusionsIndependent of a wide range of possible confounders, significant associations between infections and cognitive ability were observed. Infections or related immune responses might directly affect the cognitive ability; however, associated heritable and environmental factors might also account for the lowered cognitive ability.

Project description:Selection for sound conformation has been widely used as a primary approach to reduce lameness and leg weakness in pigs. Identification of genomic regions that affect conformation traits would help to improve selection accuracy for these lowly to moderately heritable traits. Our objective was to identify genetic factors that underlie leg and back conformation traits in three Danish pig breeds by performing a genome-wide association study followed by meta-analyses.Data on four conformation traits (front leg, back, hind leg and overall conformation) for three Danish pig breeds (23,898 Landrace, 24,130 Yorkshire and 16,524 Duroc pigs) were used for association analyses. Estimated effects of single nucleotide polymorphisms (SNPs) from single-trait association analyses were combined in two meta-analyses: (1) a within-breed meta-analysis for multiple traits to examine if there are pleiotropic genetic variants within a breed; and (2) an across-breed meta-analysis for a single trait to examine if the same quantitative trait loci (QTL) segregate across breeds. SNP annotation was implemented through Sus scrofa Build 10.2 on Ensembl to search for candidate genes.Among the 14, 12 and 13 QTL that were detected in the single-trait association analyses for the three breeds, the most significant SNPs explained 2, 2.3 and 11.4% of genetic variance for back quality in Landrace, overall conformation in Yorkshire and back quality in Duroc, respectively. Several candidate genes for these QTL were also identified, i.e. LRPPRC, WRAP73, VRTN and PPARD likely control conformation traits through the regulation of bone and muscle development, and IGF2BP2, GH1, CCND2 and MSH2 can have an influence through growth-related processes. Meta-analyses not only confirmed many significant SNPs from single-trait analyses with higher significance levels, but also detected several additional associated SNPs and suggested QTL with possible pleiotropic effects.Our results imply that conformation traits are complex and may be partly controlled by genes that are involved in bone and skeleton development, muscle and fat metabolism, and growth processes. A reliable list of QTL and candidate genes was provided that can be used in fine-mapping and marker assisted selection to improve conformation traits in pigs.

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

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

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