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Abstract:
IMPORTANCE Genetic association studies of psychiatric outcomes often
consider interactions with environmental exposures and, in particular,
apply tests that jointly consider gene and gene-environment interaction
effects for analysis. Using a genome-wide association study (GWAS) of
posttraumatic stress disorder (PTSD), we report that heteroscedasticity
(defined as variability in outcome that differs by the value of the
environmental exposure) can invalidate traditional joint tests of gene
and gene-environment interaction.
OBJECTIVES To identify the cause of bias in traditional joint tests of
gene and gene-environment interaction in a PTSD GWAS and determine
whether proposed robust joint tests are insensitive to this problem.
DESIGN, SETTING, AND PARTICIPANTS The PTSD GWAS data set consisted of
3359 individuals (978 men and 2381 women) from the Grady Trauma Project
(GTP), a cohort study from Atlanta, Georgia. The GTP performed
genome-wide genotyping of participants and collected environmental
exposures using the Childhood Trauma Questionnaire and Trauma
Experiences Inventory.
MAIN OUTCOMES AND MEASURES We performed joint interaction testing of the
Beck Depression Inventory and modified PTSD Symptom Scale in the GTP
GWAS. We assessed systematic bias in our interaction analyses using
quantile-quantile plots and genome-wide inflation factors.
RESULTS Application of the traditional joint interaction test to the GTP
GWAS yielded systematic inflation across different outcomes and
environmental exposures (inflation-factor estimates ranging from 1.07 to
1.21), whereas application of the robust joint test to the same data set
yielded no such inflation (inflation-factor estimates ranging from 1.01
to 1.02). Simulated data further revealed that the robust joint test is
valid in different heteroscedasticity models, whereas the traditional
joint test is invalid. The robust joint test also has power similar to
the traditional joint test when heteroscedasticity is not an issue.
CONCLUSIONS AND RELEVANCE We believe the robust joint test should be
used in candidate-gene studies and GWASs of psychiatric outcomes that
consider environmental interactions. To make the procedure useful for
applied investigators, we created a software tool that can be called
from the popular PLINK package for analysis.
