Meta-Analysis of Genome-Wide Association Studies with Correlated Individuals: Application to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Investigators often meta-analyze multiple genome-wide association studies (GWASs) to increase the power to detect associations of single nucleotide polymorphisms (SNPs) with a trait. Meta-analysis is also performed within a single cohort that is stratified by, e.g., sex or ancestry group. Having correlated individuals among the strata may complicate meta-analyses, limit power, and inflate Type 1 error. For example, in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), sources of correlation include genetic relatedness, shared household, and shared community. We propose a novel mixed-effect model for meta-analysis, “MetaCor,” which accounts for correlation between stratum-specific effect estimates. Simulations show that MetaCor controls inflation better than alternatives such as ignoring the correlation between the strata or analyzing all strata together in a “pooled” GWAS, especially with different minor allele frequencies (MAFs) between strata. We illustrate the benefits of MetaCor on two GWASs in the HCHS/SOL. Analysis of dental caries (tooth decay) stratified by ancestry group detected a genome-wide significant SNP (rs7791001, P-value = 3.66 × 10⁻⁸, compared to 4.67 × 10⁻⁷ in pooled), with different MAFs between strata. Stratified analysis of body mass index (BMI) by ancestry group and sex reduced overall inflation from λ_GC = 1.050 (pooled) to λ_GC = 1.028 (MetaCor). Furthermore, even after removing close relatives to obtain nearly uncorrelated strata, a naïve stratified analysis resulted in λ_GC = 1.058 compared to λ_GC = 1.027 for MetaCor.