Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.
Ontology highlight
ABSTRACT:
SUBMITTER: Lee JJ
PROVIDER: S-EPMC6393768 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
Publications
Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.
Lee James J JJ Wedow Robbee R Okbay Aysu A Kong Edward E Maghzian Omeed O Zacher Meghan M Nguyen-Viet Tuan Anh TA Bowers Peter P Sidorenko Julia J Karlsson Linnér Richard R Fontana Mark Alan MA Kundu Tushar T Lee Chanwook C Li Hui H Li Ruoxi R Royer Rebecca R Timshel Pascal N PN Walters Raymond K RK Willoughby Emily A EA Yengo Loïc L Alver Maris M Bao Yanchun Y Clark David W DW Day Felix R FR Furlotte Nicholas A NA Joshi Peter K PK Kemper Kathryn E KE Kleinman Aaron A Langenberg Claudia C Mägi Reedik R Trampush Joey W JW Verma Shefali Setia SS Wu Yang Y Lam Max M Zhao Jing Hua JH Zheng Zhili Z Boardman Jason D JD Campbell Harry H Freese Jeremy J Harris Kathleen Mullan KM Hayward Caroline C Herd Pamela P Kumari Meena M Lencz Todd T Luan Jian'an J Malhotra Anil K AK Metspalu Andres A Milani Lili L Ong Ken K KK Perry John R B JRB Porteous David J DJ Ritchie Marylyn D MD Smart Melissa C MC Smith Blair H BH Tung Joyce Y JY Wareham Nicholas J NJ Wilson James F JF Beauchamp Jonathan P JP Conley Dalton C DC Esko Tõnu T Lehrer Steven F SF Magnusson Patrik K E PKE Oskarsson Sven S Pers Tune H TH Robinson Matthew R MR Thom Kevin K Watson Chelsea C Chabris Christopher F CF Meyer Michelle N MN Laibson David I DI Yang Jian J Johannesson Magnus M Koellinger Philipp D PD Turley Patrick P Visscher Peter M PM Benjamin Daniel J DJ Cesarini David D
Nature genetics 20180723 8
Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and e ...[more]
Similar Datasets
Project description:Correlations between Educational Attainment (EA) and measures of cognitive performance are as high as 0.8. This makes EA an attractive alternative phenotype for studies wishing to map genes affecting cognition due to the ease of collecting EA data compared to other cognitive phenotypes such as IQ.In an Australian family sample of 9538 individuals we performed a genome-wide association scan (GWAS) using the imputed genotypes of ?2.4 million single nucleotide polymorphisms (SNP) for a 6-point scale measure of EA. Top hits were checked for replication in an independent sample of 968 individuals. A gene-based test of association was then applied to the GWAS results. Additionally we performed prediction analyses using the GWAS results from our discovery sample to assess the percentage of EA and full scale IQ variance explained by the predicted scores.The best SNP fell short of having a genome-wide significant p-value (p?=?9.77×10(-7)). In our independent replication sample six SNPs among the top 50 hits pruned for linkage disequilibrium (r(2)<0.8) had a p-value<0.05 but only one of these SNPs survived correction for multiple testing--rs7106258 (p?=?9.7*10(-4)) located in an intergenic region of chromosome 11q14.1. The gene based test results were non-significant and our prediction analyses show that the predicted scores explained little variance in EA in our replication sample.While we have identified a polymorphism chromosome 11q14.1 associated with EA, further replication is warranted. Overall, the absence of genome-wide significant p-values in our large discovery sample confirmed the high polygenic architecture of EA. Only the assembly of large samples or meta-analytic efforts will be able to assess the implication of common DNA polymorphisms in the etiology of EA.
| S-EPMC3111411 | biostudies-literature
Project description:The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.
| S-EPMC6372242 | biostudies-literature
Project description:We investigated the extent to which performance on standardized achievement tests, executive function (EF), and aggression in childhood and adolescence accounted for the relationship between a polygenic score for educational attainment (EA PGS) and years of education in a community sample of African Americans. Participants (N = 402; 49.9% female) were initially recruited for an elementary school-based prevention trial in a Mid-Atlantic city and followed into adulthood. In first and twelfth grade, participants completed math and reading standardized tests and teachers reported on participants' aggression and EF, specifically impulsivity and concentration problems. At age 20, participants reported on their years of education and post-secondary degrees attained and their genotype was assayed from blood or buccal swabs. An EA PGS was created using results from a large-scale GWAS on EA. A higher EA PGS was associated with higher education indirectly via adolescent achievement. No other mediating mechanisms were significant. Adolescent academic achievement is thus one mechanism through which polygenic propensity for EA influences post-secondary education among urban, African American youth.
| S-EPMC6942631 | biostudies-literature
Project description:Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
| S-EPMC4883595 | biostudies-literature
Project description:Twin and adoption studies have shown that individual differences in political participation can be explained, in part, by genetic variation. However, these research designs cannot identify which genes are related to voting or the pathways through which they exert influence, and their conclusions rely on possibly restrictive assumptions. In this study, we use three different US samples and a Swedish sample to test whether genes that have been identified as associated with educational attainment, one of the strongest correlates of political participation, predict self-reported and validated voter turnout. We find that a polygenic score capturing individuals' genetic propensity to acquire education is significantly related to turnout. The strongest associations we observe are in second-order midterm elections in the United States and European Parliament elections in Sweden, which tend to be viewed as less important by voters, parties, and the media and thus present a more information-poor electoral environment for citizens to navigate. A within-family analysis suggests that individuals' education-linked genes directly affect their voting behavior, but, for second-order elections, it also reveals evidence of genetic nurture. Finally, a mediation analysis suggests that educational attainment and cognitive ability combine to account for between 41% and 63% of the relationship between the genetic propensity to acquire education and voter turnout.
| S-EPMC8685665 | biostudies-literature
Project description:Genome-wide polygenic scores (GPS) can be used to predict individual genetic risk and resilience. For example, a GPS for years of education (EduYears) explains substantial variance in cognitive traits such as general cognitive ability and educational achievement. Personality traits are also known to contribute to individual differences in educational achievement. However, the association between EduYears GPS and personality traits remains largely unexplored. Here, we test the relation between GPS for EduYears, neuroticism, and well-being, and 6 personality and motivation domains: Academic Motivation, Extraversion, Openness, Conscientiousness, Neuroticism, and Agreeableness. The sample was drawn from a U.K.-representative sample of up to 8,322 individuals assessed at age 16. We find that EduYears GPS was positively associated with Openness, Conscientiousness, Agreeableness, and Academic Motivation, predicting between 0.6% and 3% of the variance. In addition, we find that EduYears GPS explains between 8% and 16% of the association between personality domains and educational achievement at the end of compulsory education. In contrast, both the neuroticism and well-being GPS significantly accounted for between 0.3% and 0.7% of the variance in a subset of personality domains. Furthermore, they did not significantly account for any of the covariance between the personality domains and achievement, with the exception of the neuroticism GPS explaining 5% of the covariance between Neuroticism and achievement. These results demonstrate that the genetic effects of educational attainment relate to personality traits, highlighting the multifaceted nature of EduYears GPS. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
| S-EPMC6902055 | biostudies-literature
Project description:Polygenic scores (PGS) are commonly evaluated in terms of their predictive accuracy at the population level by the proportion of phenotypic variance they explain. To be useful for precision medicine applications, they also need to be evaluated at the individual level when phenotypes are not necessarily already known. We investigated the stability of PGS in European American (EUR) and African American (AFR)-ancestry individuals from the Philadelphia Neurodevelopmental Cohort and the Adolescent Brain Cognitive Development study using different discovery genome-wide association study (GWAS) results for post-traumatic stress disorder (PTSD), type 2 diabetes (T2D), and height. We found that pairs of EUR-ancestry GWAS for the same trait had genetic correlations >0.92. However, PGS calculated from pairs of same-ancestry and different-ancestry GWAS had correlations that ranged from <0.01 to 0.74. PGS stability was greater for height than for PTSD or T2D. A series of height GWAS in the UK Biobank suggested that correlation between PGS is strongly dependent on the extent of sample overlap between the discovery GWAS. Focusing on the upper end of the PGS distribution, different discovery GWAS do not consistently identify the same individuals in the upper quantiles, with the best case being 60% of individuals above the 80th percentile of PGS overlapping from one height GWAS to another. The degree of overlap decreases sharply as higher quantiles, less heritable traits, and different-ancestry GWAS are considered. PGS computed from different discovery GWAS have only modest correlation at the individual level, underscoring the need to proceed cautiously with integrating PGS into precision medicine applications.
| S-EPMC8841810 | biostudies-literature
Project description:People who score higher on intelligence tests tend to have larger brains. Twin studies suggest the same genetic factors influence both brain size and intelligence. This has led to the hypothesis that genetics influence intelligence partly by contributing to the development of larger brains. We tested this hypothesis using four large imaging genetics studies (combined N = 7965) with polygenic scores derived from a genome-wide association study (GWAS) of educational attainment, a correlate of intelligence. We conducted meta-analysis to test associations among participants' genetics, total brain volume (i.e., brain size), and cognitive test performance. Consistent with previous findings, participants with higher polygenic scores achieved higher scores on cognitive tests, as did participants with larger brains. Participants with higher polygenic scores also had larger brains. We found some evidence that brain size partly mediated associations between participants' education polygenic scores and their cognitive test performance. Effect sizes were larger in the population-based samples than in the convenience-based samples. Recruitment and retention of population-representative samples should be a priority for neuroscience research. Findings suggest promise for studies integrating GWAS discoveries with brain imaging to understand neurobiology linking genetics with cognitive performance.
| S-EPMC6645179 | biostudies-literature
Project description:Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N???5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N???326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ?1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold?<?5?×?10-8), this corresponded, for example, to a 0.35?SD decrease in pooled reading performance per log-odds in ADHD-liability (P?=?9.2?×?10-5). Using subthreshold ADHD-instruments (P-threshold?<?0.0015), these effects became smaller, with a 0.03?SD decrease per log-odds in ADHD risk (P?=?1.4?×?10-6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.
| S-EPMC6345874 | biostudies-literature
Project description:Higher educational attainment (EA) is negatively associated with schizophrenia (SZ). However, recent studies found a positive genetic correlation between EA and SZ. We investigate possible causes of this counterintuitive finding using genome-wide association study results for EA and SZ (N = 443,581) and a replication cohort (1169 controls; 1067 cases) with deeply phenotyped SZ patients. We find strong genetic dependence between EA and SZ that cannot be explained by chance, linkage disequilibrium, or assortative mating. Instead, several genes seem to have pleiotropic effects on EA and SZ, but without a clear pattern of sign concordance. Using EA as a proxy phenotype, we isolate FOXO6 and SLITRK1 as novel candidate genes for SZ. Our results reveal that current SZ diagnoses aggregate over at least two disease subtypes: one part resembles high intelligence and bipolar disorder (BIP), while the other part is a cognitive disorder that is independent of BIP.
| S-EPMC6079028 | biostudies-literature