Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.

Manhattan Plot for GWAS of EduYears (N = 1,131,881).P values and the mean χ2 shown in figure are based on inflation-adjusted test statistics. The x-axis is chromosomal position, and the y-axis is the significance on a −log10 scale. The dashed line marks the threshold for genome-wide significance (P = 5×10−8).

Sign Concordance in Within-Family Association Analyses.The set of LD-pruned SNPs is limited to SNPs with (a) P < 5×10−3, (b) P < 5×10−5, or (c) P < 5×10−8. Each panel compares the observed sign concordance between within-family and GWAS estimates to the distributions expected (i) by chance alone (pink); (ii) according to a Bayesian framework that adjusts the GWAS estimates for bias due to winner’s curse (green); and (iii) according to the same framework with an additional adjustment for bias due to assortative mating (blue). These results are based on a GWAS sample size of 1,070,751 individuals and a within-family sample of 22,135 sibling pairs (44,270 individuals).

Tissue-specific expression of genes in DEPICT-defined loci.(a) We took microarray measurements from the Gene Expression Omnibus19 and determined whether the genes overlapping EduYears-associated loci (as defined by DEPICT) are significantly overexpressed (relative to genes in random sets of loci) in each of 180 tissues/cell types. These types are grouped in the figure by Medical Subject Headings (MeSH) first-level term. The y-axis is the one-sided P value from DEPICT on a –log10 scale. The 28 dark bars correspond to tissues/cell types in which the genes are significantly overexpressed (FDR < 0.01), including all 22 classified as part of the central nervous system (see Supplementary Table 6 for identifiers of all tissues/cell types). (b) Whereas genes prioritized by DEPICT in a previous analysis based on a smaller sample10 tend to be more strongly expressed in the brain prenatally (red curve), the 1,703 newly prioritized genes show a flat trajectory of expression across development (blue curve). Both groups of DEPICT-prioritized genes show elevated levels of expression relative to protein-coding genes that are not prioritized (gray curve). Analyses were based on RNA-seq data from the BrainSpan Developmental Transcriptome34. These results are based on the full GWAS sample of 1,131,881 individuals. Error bars represents 95% confidence intervals.

Prediction Accuracy.(a) Mean prevalence of college completion by EduYears PGS quintile. Error bars show the 95% confidence interval for the mean. (b) Incremental R2 of the EduYears PGS compared to that of other variables. (c) Incremental R2 of the PGS for EduYears and Cognitive Performance constructed from the respective GWAS or MTAG summary statistics. Error bars for the R2 values show bootstrapped 95% confidence intervals with 1000 iterations each. Sample sizes are N = 4,775 for Add Health and N = 8,609 for HRS.