Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151)

Davies, Gail; Marioni, Riccardo E.; Liewald, David C.; Hill, W. David; Hagenaars, Saskia P.; Harris, Sarah E.; Ritchie, Stuart J.; Luciano, Michelle; Fawns-Ritchie, Chloë; Lyall, Donald M.; Cullen, Breda; Cox, Simon R.; Hayward, Caroline; Porteous, David J.; Evans, Jennifer; McIntosh, Andrew M.; Gallacher, John; Craddock, Nicholas John; Pell, Jill P.; Smith, Daniel J.; Gale, Catherine; Deary, Ian J.

doi:10.1038/mp.2016.45

Cited by 340 publications

(401 citation statements)

References 74 publications

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“…Hence, it seems that the effect is caused by a certain capacity to acquire education that is not always realized. We postulate that, in addition to being correlated with cognitive ability (32,33), POLY EDU is capturing a portion of the propensity to long-term planning and delayed gratification. To address the question of whether and how these results could be extended to other populations and other time periods it should first be emphasized that the negative selection observed here is likely an example of gene-environment interaction, that is, both the direction of the effect and its magnitude could and would change given a different socioeconomic environment (5,34,35).…”

Section: Discussionmentioning

confidence: 99%

Selection against variants in the genome associated with educational attainment

Kong

Frigge

Þorleifsson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

157

111

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Epidemiological and genetic association studies show that genetics play an important role in the attainment of education. Here, we investigate the effect of this genetic component on the reproductive history of 109,120 Icelanders and the consequent impact on the gene pool over time. We show that an educational attainment polygenic score, POLY EDU, constructed from results of a recent study is associated with delayed reproduction (P < 10 −100) and fewer children overall. The effect is stronger for women and remains highly significant after adjusting for educational attainment. Based on 129,808 Icelanders born between 1910 and 1990, we find that the average POLY EDU has been declining at a rate of ∼0.010 standard units per decade, which is substantial on an evolutionary timescale. Most importantly, because POLY EDU only captures a fraction of the overall underlying genetic component the latter could be declining at a rate that is two to three times faster. selection | educational attainment | genes | fertility | sequence variants E pidemiological studies have estimated that the genetic component of educational attainment can account for as much as 40% of the trait variance (1). Recent meta-analyses (2, 3) yielded sequence variants contributing to the underlying genetic component. A negative correlation between educational attainment and number of children has been observed in many populations (4-7). A recent study of ∼20,000 genotyped Americans born between 1931 and 1953 provided direct evidence that the genetic propensity for educational attainment is associated with reduced fertility (8, 9), supporting previously postulated notions (10) that the population average of the genetic propensity for educational attainment and related traits must be declining. Here, using a population-wide sample that is both much larger and covers a substantially greater time span, and with additional auxiliary information, we aim to estimate the change of the genetic propensity of educational attainment in the Icelandic population over the last few decades, starting with an in-depth investigation of the relationship between a measurable genetic component of educational attainment and various aspects of reproduction (11)(12)(13)(14). ResultsThe number of living Icelanders is ∼317,000 (Fig. S1). A genealogical database of Icelanders (15-17) that is very close to complete for individuals born after 1910 (Materials and Methods) is used in this study. Probands used for the genetic analyses here are limited to those with both parents and all four grandparents listed in the genealogy. For the fertility studies, only children who survived their first year are counted. The first step was to use results from a recent genome-wide association study (GWAS) of educational attainment (3) to determine the per-locus allele-specific weightings of 620,000 markers used to calculate a polygenic score (18,19), POLY EDU (see Materials and Methods for details on polygenic score construction). After excluding the Icelandic cohorts in the GWAS to avoid confou...

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Section: Discussionmentioning

confidence: 99%

Selection against variants in the genome associated with educational attainment

Kong

Frigge

Þorleifsson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

157

111

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“…Bivariate GCTA-GREML 48 and linkage disequilibrium (LD) score regression 50 were used to derive genetic correlations between TMT measures and VNR in UK Biobank. 32 LD score regression was also used to estimate genetic correlations between trail making measures in UK Biobank and trail making part A, trail making part B, general cognitive function, processing speed and memory from the CHARGE consortium (participants aged 45 years or older) meta-analyses of these cognitive phenotypes. 31,33,51 Gene-based association analysis MAGMA 52 was used to derive gene-based associations using the summary results of the three GWAS for trail making.…”

Section: Snp-based Heritability and Genetic Correlationsmentioning

confidence: 99%

“…[28][29][30] A recent genome-wide association study (GWAS) of trail making part A and part B in a sample of around 6000 individuals did not find any genome-wide significant hits; 31 however, GWAS of other cognitive phenotypes have demonstrated that much larger sample sizes are required to reliably identify significant genetic loci. 32,33 Trail making is thought to have genetic influences that are shared with other cognitive abilities, with a twin-based genetic correlation of 0.48 reported between trail making, measured as the ratio between trail making part A and trail making part B, and general cognitive function, and 0.52 with working memory. 34 In addition to a relatively poor understanding of the molecular genetic underpinnings of TMT, its cognitive and psychometric architecture merits further research.…”

Section: Introductionmentioning

confidence: 99%

Genetic contributions to Trail Making Test performance in UK Biobank

et al. 2017

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The Trail Making Test (TMT) is a widely used test of executive function and has been thought to be strongly associated with general cognitive function. We examined the genetic architecture of the TMT and its shared genetic aetiology with other tests of cognitive function in 23 821 participants from UK Biobank. The single-nucleotide polymorphism-based heritability estimates for trail-making measures were 7.9% (part A), 22.4% (part B) and 17.6% (part B − part A). Significant genetic correlations were identified between trail-making measures and verbal-numerical reasoning (r g 40.6), general cognitive function (r g 40.6), processing speed (r g 40.7) and memory (r g 40.3). Polygenic profile analysis indicated considerable shared genetic aetiology between trail making, general cognitive function, processing speed and memory (standardized β between 0.03 and 0.08). These results suggest that trail making is both phenotypically and genetically strongly associated with general cognitive function and processing speed.Molecular Psychiatry advance online publication, 19 September 2017; doi:10.1038/mp.2017.189 INTRODUCTIONThe Trail Making Test (TMT) is widely used in both research and clinical settings as a test of some aspects of executive function. [1][2][3] The TMT is usually given as two parts, from which three measures are derived. In TMT Part A (TMT A), participants are required to connect an array of numbers in ascending order, by drawing a continuous line (trail) between them as quickly and accurately as possible. TMT Part B (TMT B) requires participants to connect an array of both numbers and letters in alternating ascending order (1, A, 2, B, 3, C and so on) with the same emphasis on speed and accuracy (Supplementary Figure 1). Subtracting TMT A completion time from that of TMT B (TMT B − A) is thought to allow the relative contributions of visual search and psychomotor speed to be parsed from the more complex executive functions (such as cognitive flexibility) required to alternate between numbers and letters. [4][5][6][7][8] TMT performance has been ascribed to a number of cognitive processes, 'including attention, visual search and scanning, sequencing and shifting, psychomotor speed, abstraction, flexibility, ability to execute and modify a plan of action, and ability to maintain two trains of thought simultaneously '. 9 It is considered a useful tool in research and clinical practice due to the sensitivity of the task (particularly TMT B and B − A) to frontal lobe damage (in some, but not other studies 10 ) and dementia. [11][12][13] There are declines in both TMT A and B performance in ageing. 10,[14][15][16][17][18][19][20] There is also evidence for performance deficits on TMT B in mood disorders 21 and in patients with schizophrenia and their relatives 18,[22][23][24][25][26][27] Family-based and twin-based studies have provided evidence for a genetic contribution to individual differences in trail making, estimating the heritability for trail making part A between 0.23 and 0.38, and between 0.39 and 0.65...

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“…A second POLY COG score was constructed using data from another GWAS study of educational attainment and related phenotypes (Davies et al, 2016). In this study, 1,115 SNPs reached GWAS significance, of which 15 were independent (linkage pruned) signals.…”

Section: Variant Calling and Computing Poly Cogmentioning

confidence: 99%

Holocene Selection for Variants Associated With General Cognitive Ability: Comparing Ancient and Modern Genomes

Woodley

Younuskunju

Balan³

et al. 2017

Twin Res Hum Genet

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Human populations living during the Holocene underwent considerable microevolutionary change. It has been theorized that the transition of Holocene populations into agrarianism and urbanization brought about culture-gene co-evolution that favored via directional selection genetic variants associated with higher general cognitive ability (GCA). To examine whether GCA might have risen during the Holocene, we compare a sample of 99 ancient Eurasian genomes (ranging from 4.56 to 1.21 kyr BP) with a sample of 503 modern European genomes (F st = 0.013), using three different cognitive polygenic scores (130 SNP, 9 SNP and 11 SNP). Significant differences favoring the modern genomes were found for all three polygenic scores (odds ratios = 0.92, p = 001; .81, p = 037; and .81, p = .02 respectively). These polygenic scores also outperformed the majority of scores assembled from random SNPs generated via a Monte Carlo model (between 76.4% and 84.6%). Furthermore, an indication of increasing positive allele count over 3.25 kyr was found using a subsample of 66 ancient genomes (r = 0.22, p one-tailed = .04). These observations are consistent with the expectation that GCA rose during the Holocene.

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Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151)

Cited by 340 publications

References 74 publications

Selection against variants in the genome associated with educational attainment

Selection against variants in the genome associated with educational attainment

Genetic contributions to Trail Making Test performance in UK Biobank

Holocene Selection for Variants Associated With General Cognitive Ability: Comparing Ancient and Modern Genomes

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