Meta-analysis of gene-environment interaction: Joint estimation of SNP and SNP × environment regression coefficients

Alisa K. Manning*, Michael LaValley, Ching Ti Liu, Kenneth Rice, Ping An, Yongmei Liu, Iva Miljkovic, Laura Rasmussen-Torvik, Tamara B. Harris, Michael A. Province, Ingrid B. Borecki, Jose C. Florez, James B. Meigs, L. Adrienne Cupples, Josée Dupuis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP × E) regression coefficients for use in gene-environment interaction studies. Methods: In testing SNP × E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP × E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP × E terms, and a test of homogeneity across samples. Results: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.

Original languageEnglish (US)
Pages (from-to)11-18
Number of pages8
JournalGenetic Epidemiology
Volume35
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • 2 degree of freedom meta-analysis
  • Gene-environment interaction meta-analysis
  • Joint meta-analysis
  • PPARG

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)

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