Meta-analysis of genetic association studies and adjustment for multiple testing of correlated SNPs and traits

Abstract

Meta-analysis has become a key component of well-designed genetic association studies due to the boost in statistical power achieved by combining results across multiple samples of individuals and the need to validate observed associations in independent studies. Meta-analyses of genetic association studies based on multiple SNPs and traits are subject to the same multiple testing issues as single-sample studies, but it is often difficult to adjust accurately for the multiple tests. Procedures such as Bonferroni may control the type-I error rate but will generally provide an overly harsh correction if SNPs or traits are correlated. Depending on study design, availability of individual-level data, and computational requirements, permutation testing may not be feasible in a meta-analysis framework. In this article, we present methods for adjusting for multiple correlated tests under several study designs commonly employed in meta-analyses of genetic association tests. Our methods are applicable to both prospective meta-analyses in which several samples of individuals are analyzed with the intent to combine results, and retrospective meta-analyses, in which results from published studies are combined, including situations in which (1) individual-level data are unavailable, and (2) different sets of SNPs are genotyped in different studies due to random missingness or two-stage design. We show through simulation that our methods accurately control the rate of type I error and achieve improved power over multiple testing adjustments that do not account for correlation between SNPs or traits.

Figure 1

−log₁₀ of P_ACT-adjusted P-values plotted against theoretical quantiles (diagonal line) with 95% confidence intervals (curved lines). P-values are from 5000 simulated meta-analyses where 59 SNPs were tested for association with 4 traits A) in 6 studies under a prospective design where individual-level data were available, or B) in 6 studies under a retrospective design where only summary statistics were available, or C) in an initial study under a two-stage design where only tests with P<.10 were followed up in 5 additional studies.

Figure 1

−log₁₀ of P_ACT-adjusted P-values plotted against theoretical quantiles (diagonal line) with 95% confidence intervals (curved lines). P-values are from 5000 simulated meta-analyses where 59 SNPs were tested for association with 4 traits A) in 6 studies under a prospective design where individual-level data were available, or B) in 6 studies under a retrospective design where only summary statistics were available, or C) in an initial study under a two-stage design where only tests with P<.10 were followed up in 5 additional studies.

Figure 1

−log₁₀ of P_ACT-adjusted P-values plotted against theoretical quantiles (diagonal line) with 95% confidence intervals (curved lines). P-values are from 5000 simulated meta-analyses where 59 SNPs were tested for association with 4 traits A) in 6 studies under a prospective design where individual-level data were available, or B) in 6 studies under a retrospective design where only summary statistics were available, or C) in an initial study under a two-stage design where only tests with P<.10 were followed up in 5 additional studies.

Figure A.1

Comparison of P_ACT-2s estimated for 8 correlated tests as either a piecewise sum of probabilities or a faster 2-step approximation.