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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).

TitleMeta-Analysis of Genome-Wide Association Studies with Correlated Individuals: Application to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).
Publication TypePublication
Year2016
AuthorsSofer T, Shaffer JR, Graff M, Qi Q, Stilp AM, Gogarten SM, North KE, Isasi CR, Laurie CC, Szpiro AA
JournalGenet Epidemiol
Volume40
Issue6
Pagination492-501
Date Published2016 09
ISSN1098-2272
KeywordsBody mass index, Dental Caries, Gene Frequency, genome-wide association study, Hispanic Americans, Humans, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide, Public Health
Abstract

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.

DOI10.1002/gepi.21981
Alternate JournalGenet Epidemiol
PubMed ID27256683
PubMed Central IDPMC4981554
Grant ListHHSN268201300005C / HL / NHLBI NIH HHS / United States
N01HC65236 / HL / NHLBI NIH HHS / United States
N01HC65235 / HL / NHLBI NIH HHS / United States
N01HC65234 / HL / NHLBI NIH HHS / United States
K01 HL129892 / HL / NHLBI NIH HHS / United States
N01HC65233 / HL / NHLBI NIH HHS / United States
R01 DK101855 / DK / NIDDK NIH HHS / United States
N01HC65237 / HL / NHLBI NIH HHS / United States
UL1 TR001073 / TR / NCATS NIH HHS / United States
MS#: 
0388
Manuscript Lead/Corresponding Author Affiliation: 
HCHS/SOL Genetic Analysis Center - University of Washington, Seattle
ECI: 
Manuscript Status: 
Published