Dataset Information

Detecting maternal-fetal genotype interactions associated with conotruncal heart defects: a haplotype-based analysis with penalized logistic regression.

ABSTRACT: Nonsyndromic congenital heart defects (CHDs) develop during embryogenesis as a result of a complex interplay between environmental exposures, genetics, and epigenetic causes. Genetic factors associated with CHDs may be attributed to either independent effects of maternal or fetal genes, or the intergenerational interactions between maternal and fetal genes. Detecting gene-by-gene interactions underlying complex diseases is a major challenge in genetic research. Detecting maternal-fetal genotype (MFG) interactions and differentiating them from the maternal/fetal main effects has presented additional statistical challenges due to correlations between maternal and fetal genomes. Traditionally, genetic variants are tested separately for maternal/fetal main effects and MFG interactions on a single-locus basis. We conducted a haplotype-based analysis with a penalized logistic regression framework to dissect the genetic effect associated with the development of nonsyndromic conotruncal heart defects (CTD). Our method allows simultaneous model selection and effect estimation, providing a unified framework to differentiate maternal/fetal main effect from the MFG interaction effect. In addition, the method is able to test multiple highly linked SNPs simultaneously with a configuration of haplotypes, which reduces the data dimensionality and the burden of multiple testing. By analyzing a dataset from the National Birth Defects Prevention Study (NBDPS), we identified seven genes (GSTA1, SOD2, MTRR, AHCYL2, GCLC, GSTM3, and RFC1) associated with the development of CTDs. Our findings suggest that MFG interactions between haplotypes in three of seven genes, GCLC, GSTM3, and RFC1, are associated with nonsyndromic conotruncal heart defects.

SUBMITTER: Li M

PROVIDER: S-EPMC4043210 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Detecting maternal-fetal genotype interactions associated with conotruncal heart defects: a haplotype-based analysis with penalized logistic regression.

Li Ming M Erickson Stephen W SW Hobbs Charlotte A CA Li Jingyun J Tang Xinyu X Nick Todd G TG Macleod Stewart L SL Cleves Mario A MA

Genetic epidemiology 20140302 3

Nonsyndromic congenital heart defects (CHDs) develop during embryogenesis as a result of a complex interplay between environmental exposures, genetics, and epigenetic causes. Genetic factors associated with CHDs may be attributed to either independent effects of maternal or fetal genes, or the intergenerational interactions between maternal and fetal genes. Detecting gene-by-gene interactions underlying complex diseases is a major challenge in genetic research. Detecting maternal-fetal genotype ...[more]

PMID: 24585533

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Project description:Gene-environment (G × E) interactions are biologically important for a wide range of environmental exposures and clinical outcomes. Because of the large number of potential interactions in genomewide association data, the standard approach fits one model per G × E interaction with multiple hypothesis correction (MHC) used to control the type I error rate. Although sometimes effective, using one model per candidate G × E interaction test has two important limitations: low power due to MHC and omitted variable bias. To avoid the coefficient estimation bias associated with independent models, researchers have used penalized regression methods to jointly test all main effects and interactions in a single regression model. Although penalized regression supports joint analysis of all interactions, can be used with hierarchical constraints, and offers excellent predictive performance, it cannot assess the statistical significance of G × E interactions or compute meaningful estimates of effect size. To address the challenge of low power, researchers have separately explored screening-testing, or two-stage, methods in which the set of potential G × E interactions is first filtered and then tested for interactions with MHC only applied to the tests actually performed in the second stage. Although two-stage methods are statistically valid and effective at improving power, they still test multiple separate models and so are impacted by MHC and biased coefficient estimation. To remedy the challenges of both poor power and omitted variable bias encountered with traditional G × E interaction detection methods, we propose a novel approach that combines elements of screening-testing and hierarchical penalized regression. Specifically, our proposed method uses, in the first stage, an elastic net-penalized multiple logistic regression model to jointly estimate either the marginal association filter statistic or the gene-environment correlation filter statistic for all candidate genetic markers. In the second stage, a single multiple logistic regression model is used to jointly assess marginal terms and G × E interactions for all genetic markers that pass the first stage filter. A single likelihood-ratio test is used to determine whether any of the interactions are statistically significant. We demonstrate the efficacy of our method relative to alternative G × E detection methods on a bladder cancer data set.

Project description:BackgroundThere is a growing awareness that interaction between multiple genes play an important role in the risk of common, complex multi-factorial diseases. Many common diseases are affected by certain genotype combinations (associated with some genes and their interactions). The identification and characterization of these susceptibility genes and gene-gene interaction have been limited by small sample size and large number of potential interactions between genes. Several methods have been proposed to detect gene-gene interaction in a case control study. The penalized logistic regression (PLR), a variant of logistic regression with L2 regularization, is a parametric approach to detect gene-gene interaction. On the other hand, the Multifactor Dimensionality Reduction (MDR) is a nonparametric and genetic model-free approach to detect genotype combinations associated with disease risk.MethodsWe compared the power of MDR and PLR for detecting two-way and three-way interactions in a case-control study through extensive simulations. We generated several interaction models with different magnitudes of interaction effect. For each model, we simulated 100 datasets, each with 200 cases and 200 controls and 20 SNPs. We considered a wide variety of models such as models with just main effects, models with only interaction effects or models with both main and interaction effects. We also compared the performance of MDR and PLR to detect gene-gene interaction associated with acute rejection(AR) in kidney transplant patients.ResultsIn this paper, we have studied the power of MDR and PLR for detecting gene-gene interaction in a case-control study through extensive simulation. We have compared their performances for different two-way and three-way interaction models. We have studied the effect of different allele frequencies on these methods. We have also implemented their performance on a real dataset. As expected, none of these methods were consistently better for all data scenarios, but, generally MDR outperformed PLR for more complex models. The ROC analysis on the real dataset suggests that MDR outperforms PLR in detecting gene-gene interaction on the real dataset.ConclusionAs one might expect, the relative success of each method is context dependent. This study demonstrates the strengths and weaknesses of the methods to detect gene-gene interaction.

Dataset Information

Detecting maternal-fetal genotype interactions associated with conotruncal heart defects: a haplotype-based analysis with penalized logistic regression.

Publications

Detecting maternal-fetal genotype interactions associated with conotruncal heart defects: a haplotype-based analysis with penalized logistic regression.

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