title: Correcting systematic inflation in genetic association tests that consider interaction effects: application to a genome-wide association study of posttraumatic stress disorder.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Almli
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Richard
authors.initials: R
authors.lastname: Duncan
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Statistics, Pennsylvania State University, State College.
authors.forename: Debashis
authors.initials: D
authors.lastname: Ghosh
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia4Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia5Mental Health Service Line, Department of Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Bekh
authors.initials: B
authors.lastname: Bradley
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Epstein
mesh_terms: D000328:Adult; D015982:Bias; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D015233:Models, Statistical; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics*; D055815:Young Adult