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

Genet Epidemiol. 2016 Sep;40(6):492-501. doi: 10.1002/gepi.21981. Epub 2016 Jun 3.


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 λGC=1.050 (pooled) to λGC=1.028 (MetaCor). Furthermore, even after removing close relatives to obtain nearly uncorrelated strata, a naïve stratified analysis resulted in λGC=1.058 compared to λGC=1.027 for MetaCor.

Keywords: effect heterogeneity; inflation; mixed models; stratified analysis.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Body Mass Index
  • Dental Caries / genetics
  • Dental Caries / pathology
  • Gene Frequency
  • Genome-Wide Association Study*
  • Hispanic or Latino / genetics*
  • Humans
  • Models, Genetic
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Public Health