Gene-environment interaction testing in family-based association studies with phenotypically ascertained samples: a causal inference approach.
ABSTRACT We propose a method for testing gene-environment (G × E) interactions on a complex trait in family-based studies in which a phenotypic ascertainment criterion has been imposed. This novel approach employs G-estimation, a semiparametric estimation technique from the causal inference literature, to avoid modeling of the association between the environmental exposure and the phenotype, to gain robustness against unmeasured confounding due to population substructure, and to acknowledge the ascertainment conditions. The proposed test allows for incomplete parental genotypes. It is compared by simulation studies to an analogous conditional likelihood-based approach and to the QBAT-I test, which also invokes the G-estimation principle but ignores ascertainment. We apply our approach to a study of chronic obstructive pulmonary disorder.
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ABSTRACT: The interest in performing gene-environment interaction studies has seen a significant increase with the increase of advanced molecular genetics techniques. Practically, it became possible to investigate the role of environmental factors in disease risk and hence to investigate their role as genetic effect modifiers. The understanding that genetics is important in the uptake and metabolism of toxic substances is an example of how genetic profiles can modify important environmental risk factors to disease. Several rationales exist to set up gene-environment interaction studies and the technical challenges related to these studies-when the number of environmental or genetic risk factors is relatively small-has been described before. In the post-genomic era, it is now possible to study thousands of genes and their interaction with the environment. This brings along a whole range of new challenges and opportunities. Despite a continuing effort in developing efficient methods and optimal bioinformatics infrastructures to deal with the available wealth of data, the challenge remains how to best present and analyze genome-wide environmental interaction (GWEI) studies involving multiple genetic and environmental factors. Since GWEIs are performed at the intersection of statistical genetics, bioinformatics and epidemiology, usually similar problems need to be dealt with as for genome-wide association gene-gene interaction studies. However, additional complexities need to be considered which are typical for large-scale epidemiological studies, but are also related to "joining" two heterogeneous types of data in explaining complex disease trait variation or for prediction purposes.Human Genetics 07/2012; 131(10):1591-613. · 4.63 Impact Factor
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ABSTRACT: Over the past three decades, substantial developments have been made on how to infer the causal effect of an exposure on an outcome, using data from observational studies, with the randomized experiment as the golden standard. These developments have reshaped the paradigm of how to build statistical models, how to adjust for confounding, how to assess direct effects, mediated effects and interactions, and even how to analyze data from randomized experiments. The congruence of random transmission of alleles during meiosis and the randomization in controlled experiments/trials, suggests that genetic studies may lend themselves naturally to a causal analysis. In this contribution, we will reflect on this and motivate, through illustrative examples, where insights from the causal inference literature may help to understand and correct for typical biases in genetic effect estimates.Human Genetics 08/2012; 131(10):1665-76. · 4.63 Impact Factor