Estimating genetic effect sizes under joint disease-endophenotype models in presence of gene-environment interactions.
Effects of genetic variants on the risk of complex diseases estimated from association studies are typically small. Nonetheless, variants may have important effects in presence of specific levels of environmental exposures, and when a trait related to the disease (endophenotype) is either normal or impaired. We propose polytomous and transition models to represent the relationship between disease, endophenotype, genotype and environmental exposure in family studies. Model coefficients were estimated using generalized estimating equations and were used to derive gene-environment interaction effects and genotype effects at specific levels of exposure. In a simulation study, estimates of the effect of a genetic variant were substantially higher when both an endophenotype and an environmental exposure modifying the variant effect were taken into account, particularly under transition models, compared to the alternative of ignoring the endophenotype. Illustration of the proposed modeling with the metabolic syndrome, abdominal obesity, physical activity and polymorphisms in the NOX3 gene in the Quebec Family Study revealed that the positive association of the A allele of rs1375713 with the metabolic syndrome at high levels of physical activity was only detectable in subjects without abdominal obesity, illustrating the importance of taking into account the abdominal obesity endophenotype in this analysis.
Laboratoire de Biostatistique et Psychiatrie Génétique, Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec Québec, QC, Canada ; Département de Médecine Sociale et Préventive, Université Laval Québec, QC, Canada.
Alexandre
A
Bureau
Laboratoire de Biostatistique et Psychiatrie Génétique, Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec Québec, QC, Canada.
Jordie
J
Croteau
Département de Kinésiologie, Université Laval Québec, QC, Canada.
Christian
C
Couture
Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval Québec, QC, Canada ; École de Nutrition, Université Laval Québec, QC, Canada.
Marie-Claude
MC
Vohl
Human Genomics Laboratory, Pennington Biomedical Research Center Baton Rouge, LA, USA.
Claude
C
Bouchard
Département de Kinésiologie, Université Laval Québec, QC, Canada ; Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval Québec, QC, Canada.
Louis
L
Pérusse
abdominal obesity; endophenotype; familial association studies; generalized estimating equations; metabolic syndrome; physical activity; polytomous logistic model; transition model