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Meta‐Analysis of Genome‐Wide Association Studies with Correlated Individuals: Application to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Author(s) -
Sofer Tamar,
Shaffer John R.,
Graff Mariaelisa,
Qi Qibin,
Stilp Adrienne M.,
Gogarten Stephanie M.,
North Kari E.,
Isasi Carmen R.,
Laurie Cathy C.,
Szpiro Adam A.
Publication year - 2016
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/gepi.21981
Subject(s) - genome wide association study , association (psychology) , demography , meta analysis , biology , gerontology , genetics , psychology , medicine , single nucleotide polymorphism , sociology , genotype , gene , psychotherapist
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 − 7in pooled), with different MAFs between strata. Stratified analysis of body mass index (BMI) by ancestry group and sex reduced overall inflation fromλ G C = 1.050 (pooled) toλ G C = 1.028 (MetaCor). Furthermore, even after removing close relatives to obtain nearly uncorrelated strata, a naïve stratified analysis resulted inλ G C = 1.058 compared toλ G C = 1.027 for MetaCor.