Replicability and robustness of genome-wide-association studies for behavioral traits

Abstract

A recent genome-wide-association study of educational attainment identified three single-nucleotide polymorphisms (SNPs) whose associations, despite their small effect sizes (each R (2) ≈ 0.02%), reached genome-wide significance (p < 5 × 10(-8)) in a large discovery sample and were replicated in an independent sample (p < .05). The study also reported associations between educational attainment and indices of SNPs called "polygenic scores." In three studies, we evaluated the robustness of these findings. Study 1 showed that the associations with all three SNPs were replicated in another large (N = 34,428) independent sample. We also found that the scores remained predictive (R (2) ≈ 2%) in regressions with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered genome-wide-association studies can identify replicable genetic associations with behavioral traits. The small effect sizes of individual SNPs are likely to be a major contributing factor explaining the striking contrast between our results and the disappointing replication record of most candidate-gene studies.

Keywords: behavior genetics; educational attainment; genome-wide association study; individual differences; population stratification.

Figure 1

Comparison of effect sizes across studies Notes: Panel A shows the (absolute value of the) effect on years of schooling of a change in one reference allele for each of the three individual SNPs, with 95% confidence intervals. The results are a visual representation of the numbers in Table 1. Panel B shows the (absolute value of the) effect on years of schooling of a change in one standard deviation of the polygenic score that includes all SNPs, with 95% confidence intervals. The results for QIMR and STR are a visual representation of the numbers in the “all SNPs” columns of Tables 2. Similarly for the results for FHS and the “all SNPs” column of Table 3 (but note that the score in FHS is not comparable with the other two scores, since it is based on fewer SNPs).