Strategy for Detecting Susceptibility Genes with Weak or No Marginal Effect

Most human diseases result from complex interactions among multiple genes that yield weak or modest effects. Despite the growing awareness of the importance of genegene interactions, the paradigm of detectable effects of individual variants remains the cornerstone of genome association studies with...

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Bibliographic Details
Published in:Human heredity 2007-01, Vol.63 (2), p.85-92
Main Authors: Kotti, S., Bickeböller, H., Clerget-Darpoux, F.
Format: Article
Language:English
Subjects:
Epistasis, Genetic
Genes - genetics
Genetic Diseases, Inborn - genetics
Genetic Markers - genetics
Genetic Predisposition to Disease - genetics
Genetics
Genomics
Genotype
Heredity
Humans
Life Sciences
Likelihood Functions
Models, Genetic
Original Paper
Penetrance
Polymorphism, Single Nucleotide - genetics
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Summary:Most human diseases result from complex interactions among multiple genes that yield weak or modest effects. Despite the growing awareness of the importance of genegene interactions, the paradigm of detectable effects of individual variants remains the cornerstone of genome association studies with tagSNPs. The interactive effect of two variants is only tested once the individual effect of one variant is detected. Both genes, however, may have at the same time a weak (or even no) marginal effect but an important effect through their interaction. In such a situation, current approaches may fail to detect variants having a crucial role in the causal chain. Here, we propose a new strategy: the 2-locus TDT. It allows the detection of the involvement of two genes without individual effect. Our strategy simultaneously uses information on biallelic candidate polymorphisms in two genes M and N. We first estimate the relative marginal penetrances of the genotype at each locus and of the joint (two-locus) genotype and then we test for the interactive effect of the two genes using a likelihood ratio test. We show that our approach has good power to detect the effect of two genes in situations for which a locus-by-locus strategy would have been unsuccessful. At a time where genomewide association studies are fashionable, we think it is important to consider the strategy of studying good candidate pathways with our approach.
ISSN:0001-5652
1423-0062
DOI:10.1159/000099180